Cancers doi: 10.20517/cdr.2025.14

Authors: Jinglu Yu,Xiaoni Kong,Yu Feng

Non-small cell lung cancer (NSCLC) represents a formidable challenge in oncology due to its molecular heterogeneity and the dynamic suppressive nature of its tumor microenvironment (TME). Despite the transformative impact of immune checkpoint inhibitors (ICIs) on cancer therapy, the majority of NSCLC patients experience resistance, necessitating novel approaches to overcome immune evasion. This review highlights shared and subtype-specific mechanisms of immune resistance within the TME, including metabolic reprogramming, immune cell dysfunction, and physical barriers. Beyond well-characterized components such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, emerging players - neutrophil extracellular traps, tertiary lymphoid structures, and exosomal signaling networks - underscore the TME’s complexity and adaptability. A multi-dimensional framework is proposed to transform cold, immune-excluded tumors into hot, immune-reactive ones. Key strategies include enhancing immune infiltration, modulating immunosuppressive networks, and activating dormant immune pathways. Cutting-edge technologies, such as single-cell sequencing, spatial transcriptomics, and nanomedicine, are identified as pivotal tools for decoding TME heterogeneity and personalizing therapeutic interventions. By bridging mechanistic insights with translational innovations, this review advocates for integrative approaches that combine ICIs with metabolic modulators, vascular normalizers, and emerging therapies such as STING agonists and tumor vaccines. The synergistic potential of these strategies is poised to overcome resistance and achieve durable antitumor immunity. Ultimately, this vision underscores the importance of interdisciplinary collaboration and real-time TME profiling in refining precision oncology for NSCLC, offering a blueprint for extending these advances to other malignancies.

Cancers doi: 10.20517/cdr.2025.51

Authors: Mengqing Chen,Lin Huang,Simei Zhao,Mengna Zhu,Si Sun,Wenhan Li,Jing Cai,Minggang Peng,Yiping Wen,Zehua Wang

Aim: Cancer stem cells (CSCs) are pivotal in mediating platinum resistance in ovarian cancer. This study aimed to screen compounds sensitizing CSCs to cisplatin by using a small molecule inhibitor library.

Methods: A library of 105 common drugs was screened in ovarian CSC model SK-3rd and ovarian cancer platinum-resistant cell model SKDDP to identify those that could enhance sensitivity to cisplatin by MTT assay. The antitumor effect was assessed in ovarian cancer cells using the MTT assay, colony formation assay, and apoptosis assay. The impact on cancer cell stemness was evaluated using qPCR and Sphere-forming assays. Finally, the effect of the combination regimen was evaluated in patient-derived organoids (PDOs) under different treatments by the CellTiter-Glo Luminescence Assay.

Results: The results of the initial screening on SK-3rd identified five candidate compounds. Rescreening on SKDDP showed that Ivosidenib was the most effective in sensitizing cisplatin. MTT, colony formation, and apoptosis assays demonstrated that Ivosidenib enhanced the sensitivity to cisplatin, inhibited proliferation, and induced apoptosis in ovarian cancer cells, including SK-3rd and SKDDP. Furthermore, Ivosidenib lowered stemness marker expression and countered CSC enrichment caused by platinum-based chemotherapy in ovarian cancer cells. Finally, the synergistic effect of this combination was also confirmed in three ovarian cancer PDOs.

Conclusion: Ivosidenib may increase cisplatin sensitivity in ovarian cancer cells by decreasing their stemness, providing a potential therapeutic method for ovarian cancer patients.

Cancers doi: 10.20517/cdr.2024.212

Authors: Maria Stella Franzè, Francesca Saffioti, Vasileios K. Mavroeidis

Hepatocellular carcinoma (HCC) is a malignant tumor originating from hepatocytes, often developing against a backdrop of chronic inflammation and liver fibrosis. The primary risk factor for HCC is cirrhosis, and early detection is crucial for improving outcomes. Despite advances in treatment, the prognosis remains poor, with a 5-year survival rate of approximately 15%-38%. Growing evidence highlights the critical role of the tumor microenvironment (TME) in modulating tumor initiation, growth, progression, and, in some cases, suppression. The TME is a complex ecosystem composed of immune cells, cancer-associated fibroblasts, extracellular matrix components, and other factors such as growth factors and cytokines. By shaping tumor cell behavior, the TME facilitates immune evasion and contributes to resistance to treatment. Tumor-associated immune cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, contribute to immune suppression and progression. On the other hand, immune activation via immune checkpoint inhibition has shown promise in improving outcomes, especially when combined with other treatments such as transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), and systemic therapies. Studies have demonstrated the potential of targeting the TME to enhance treatment efficacy, with immune modulation emerging as a key therapeutic strategy. This review explores the complex interactions within the TME in HCC, highlighting its role in therapy resistance and immune evasion. It also discusses current therapeutic approaches to target the TME to improve clinical outcomes in HCC patients.

Cancers doi: 10.20517/cdr.2024.208

Authors: Ivan Li, Yuchen Huo, Ting Yang, Howard Gunawan, Ludmil B. Alexandrov, Peter E. Zage

Aim: The fibroblast growth factor receptor (FGFR) family receptors regulate cell proliferation, survival, and migration and are linked to cancer drug resistance. FGFR gene family alterations have been found in multiple adult cancers, for which FGFR inhibitors are in various stages of clinical development. This study aimed to delineate the FGFR alterations in pediatric tumors and provide a preclinical rationale for developing FGFR inhibitors for select pediatric patients.

Methods: The prevalence of FGFR alterations in pediatric cancers was calculated from databases with available pediatric tumor data. Effects of the pan-FGFR inhibitor infigratinib (BGJ398) on pediatric cancer cell line viability and migration were evaluated by continuous live cell imaging and compared to FGFR gene expression. Effects on cell death and signaling pathway activity were evaluated by live cell imaging and Western blots.

Results: Overall rates of FGFR1-4 gene alterations in pediatric cancers were rare, and the mutation profile substantially differs from that of adult tumors. Although FGFR genomic alterations are rare in pediatric neuroblastoma tumors, overexpression of FGFR1-4 is observed in tumor subsets and is associated with outcomes. Dose-dependent inhibition of cell proliferation and migration and promotion of cell death were achieved with BGJ398 treatment in neuroblastoma cell lines, accompanied by inhibition of RAS-MAPK pathway activity and induction of apoptosis.

Conclusion: Adult and pediatric cancers share common mechanisms of FGFR activation but differ in overall alteration rates and relative abundance of specific aberrations. Preliminary experimental data indicate the therapeutic potential of FGFR inhibitors and suggest mechanisms of resistance in the treatment of pediatric cancers.

Cancers doi: 10.20517/cdr.2024.189

Authors: Nolan M. Stubbs, Tyler J. Roady, Maximilian P. Schwermann, Elias O. Eteshola, William J. MacDonald, Connor Purcell, Dinara Ryspayeva, Nataliia Verovkina, Vida Tajiknia, Maryam Ghandali, Viva Voong, Alexis J. Lannigan, Alexander G. Raufi, Sean Lawler, Sheldon L. Holder, Benedito A. Carneiro, Liang Cheng, Howard P. Safran, Stephanie L. Graff, Don S. Dizon, Sendurai A. Mani, Attila A. Seyhan, Robert W. Sobol, Eric T. Wong, Clark C. Chen, Ziya Gokaslan, Martin S. Taylor, Brian M. Rivers, Wafik S. El-Deiry

Acquired resistance to molecularly targeted therapies remains a formidable challenge in the treatment of cancer, despite significant advancements over the last several decades. We critically evaluate the evolving landscape of resistance mechanisms to targeted cancer therapies, with a focus on the genetic, molecular, and environmental contributors across a variety of malignancies. Intrinsic mechanisms such as mutations, drug and drug target modifications, and, notably, the activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways are mechanisms different malignancies use to combat therapeutic effectiveness. Furthermore, extrinsic alterations to the tumor microenvironment contribute to therapeutic resistance. We highlight similarities and differences in mechanisms across a wide spectrum of cancers including hematologic malignancies, non-small cell lung cancer, gastrointestinal, breast, and prostate cancers, pancreatic, ovarian, endometrial, and intracranial gliomas. Emerging strategies to overcome resistance, including multi-targeted approaches, combination therapies, and exploitation of synthetic lethality, are all critically discussed. We advocate for a nuanced understanding of resistance mechanisms as a cornerstone for developing future therapeutic strategies, emphasizing the necessity for integrated approaches that encompass genomic insights and precision medicine to outpace the dynamic and complex nature of cancer evolution and therapy resistance.

Cancers doi: 10.20517/cdr.2024.193

Authors: Mariarosaria Negri, Feliciana Amatrudo, Donatella Paola Provvisiero, Roberta Patalano, Giovanna Trinchese, Fabiano Cimmino, Cristina de Angelis, Chiara Simeoli, Renata Simona Auriemma, Maria Pina Mollica, Annamaria Colao, Rosario Pivonello, Claudia Pivonello

Aim: The current in vitro study investigated the role of Period 2 (PER2) in aggressiveness and the acquisition of drug resistance in hepatocellular carcinoma (HCC).

Methods: Parental PLC/PRF/5 cells, along with everolimus-resistant (EveR) and Sorafenib-resistant (SorR) cell lines, were used in this study. PER2 expression was silenced using siRNA knockdown (KD) and blocked using CRISPR/Cas9 Plasmid knockout (KO). PER2 expression levels were assessed by quantitative real-time reverse transcription polymerase chain reaction and immunofluorescence, together with markers of epithelial-mesenchymal transition, casein kinase 1ε (CK1ε), and tumor protein p53. Modulation of p53, p21, cellular myelocytomatosis oncogene, and mouse double minute 2 homolog was investigated by western blot. Mitochondrial activity was evaluated using the Seahorse System. The role of PER2 on the onset of aggressiveness was examined through assays of cell proliferation, migration, and colony formation.

Results: PLC/PRF/5 everolimus-resistant (EveR), SorR, PER2 KD, and PER2 KO cells expressed significantly lower PER2 mRNA and protein levels compared to the parental PLC/PRF/5 cells. Remarkably, in PLC/PRF/5 EveR and SorR cells, PER2 protein was entirely localized in the cytoplasm, where it colocalized with CK1ε, in contrast to the parental cells. In PLC/PRF/5 EveR, PER2 KD and PER2 KO cells, but not in SorR cells, E-cadherin was significantly decreased while vimentin and ZEB1 protein levels were significantly increased across all modified cell models. Interestingly, p53 expression was reduced in PER2 KO cells and completely absent in PLC/PRF/5 EveR and SorR cells. Consistent with these findings, the inhibitory effect of everolimus (10^-9 M) and sorafenib (5 × 10^-6 M) on cell proliferation, migration, and colony formation observed in parental PLC/PRF/5 cells were reversed in PER2 KD and KO cells, which was accompanied by upregulation of oncogenes, downregulation of tumor suppressor genes, and alterations in mitochondrial activity.

Conclusion: These results suggest that the acquisition of an aggressive phenotype is characterized by reduced PER2 expression and loss of its nuclear translocation, which, in turn, is associated with resistance to systemic therapy in hepatocellular carcinoma.

Cancers doi: 10.20517/cdr.2024.206

Authors: Yunhuan Liu, Yong Yu, Congli Hu, Minlin Jiang, Chao Zhao, Xuefei Li, Lei Cheng, Caicun Zhou

Aim: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment approach for NSCLC. However, the effectiveness of ICI therapy in patients with EGFR-driven NSCLC, particularly those resistant to EGFR-TKI, has been disappointing. The immunosuppressive tumor microenvironment (TME) following EGFR-TKI therapy has been proved to significantly affected the effectiveness of ICIs. Therefore, studying the mechanism behind the development of a suppressive TME and exploring potential interventions is crucial for research on EGFR-TKI-resistant NSCLC.

Methods: ZEB2 levels were quantified in human NSCLC cell lines and in tumor specimens from NSCLC patients by quantitative RT-PCR (qRT-PCR), WB, and immunohistochemical staining. To examine how ZEB2 affected macrophage polarization, M1/M2 marker profiles were measured with qRT-PCR and flow cytometry. Changes in cytokine production triggered by altered ZEB2 expression were determined with qRT-PCR, ELISA, and Meso Scale Discovery electrochemiluminescence assays. The direct binding of ZEB2 to cytokine-gene promoters was tested using a dual-luciferase reporter system. Upstream regulatory pathways were investigated by correlating LUAD transcriptomic data from TCGA with ZEB2 expression and validating key findings via western blotting. Finally, cell-derived xenograft (CDX) models were generated by subcutaneously implanting pre-treated PC9 or HCC827 cells into BALB/c nude mice to verify the impact of EGFR-TKI resistance and ZEB2 on tumor-associated macrophage (TAM) polarization in vivo.

Results: It was elucidated that EGFR-TKI resistance upregulated the M2 polarization biomarkers, Arg-1 (PC9-GR: P < 0.01; HCC827-GR: P < 0.05) and IL4 (PC9-GR: P < 0.01; HCC827-GR: P < 0.01), while downregulated the M1 polarization biomarkers, TNF-α (PC9-GR: P < 0.01; HCC827-GR: P < 0.01), IL1β (PC9-GR: P < 0.01; HCC827-GR: P < 0.01), and IL6(PC9-GR: P < 0.001; HCC827-GR: P < 0.001) in NSCLC cell lines. Meanwhile, CD206⁺ TAMs (PC9-GR:P < 0.05; HCC827-GR: P < 0.01) were increased and CD86⁺ TAMs (PC9-GR: P < 0.05; HCC827-GR: P < 0.05) were decreased in both EGFR-TKI-resistant mice models. Apart from the formation of suppressive TME, ZEB2 was found to be upregulated in PC9-GR (qRT-PCR: P < 0.0001; WB: P < 0.05) and HCC827-GR (qRT-PCR: P < 0.0001; WB: P < 0.05) cells. The same trend was also noticed in clinical samples, with ZEB2 upregulated after gefitinib resistance in NSCLC patients (P < 0.0001). Based on these findings, ZEB2 knockdown was proved to downregulate Arg-1 (PC9-GR: P < 0.01; HCC827-GR: P < 0.05) and IL4 (PC9-GR: P < 0.01; HCC827-GR: P < 0.001), while upregulate the TNF-α (PC9-GR: P < 0.0001; HCC827-GR: P < 0.0001), IL1β (HCC827-GR: P < 0.001), and IL6 (PC9-GR: P < 0.01; HCC827-GR: P < 0.001), indicating its role in M1/M2 polarization in both EGFR-TKI-resistant NSCLC cell lines. The downregulation of CD206⁺ TAMs (PC9-GR: P < 0.05; HCC827-GR: P < 0.01) and the upregulation of CD86⁺ TAMs (PC9-GR: P < 0.001; HCC827-GR: P < 0.05) also demonstrated the reversion of suppressive TME after ZEB2 knockout in EGFR-TKI-resistant mice models. Additionally, after the intervention of MK2206, which was an Akt inhibitor, ZEB2 expression was suppressed at both low (PC9-GR: P < 0.001; HCC827-GR:P < 0.001) and high concentrations (PC9-GR: P < 0.001; HCC827-GR: P < 0.0001). Finally, the mechanism underlying ZEB2’s regulation on TAM polarization was proved to be associated with cytokine secretion. According to the results of ELISA, apart from its inducement on TGF-β1 secretion (PC9-GR: P < 0.0001; HCC827-GR: P < 0.0001), ZEB2 could directly bind to the promoter region of CSF-1 to elevate its secretion (PC9-GR:P < 0.0001; HCC827-GR: P < 0.0001).

Conclusion: In EGFR-TKI-resistant NSCLC, activation of the PI3K-Akt cascade drove a marked rise in ZEB2 expression. The elevated ZEB2 increased CSF-1 and TGF-β1 release, steering macrophages toward an M2 phenotype while impeding M1 polarization. Accordingly, suppressing ZEB2 had the potential to reshape the TME and enhance the effectiveness of ICIs once EGFR-TKI resistance had emerged.

Cancers doi: 10.20517/cdr.2024.181

Authors: Yujie Shi, Lexia Chen, Qiong Cheng, Peijia Niu, Yahan Weng, Xiaohe Yang

Aim: Resistance to PI3K inhibitor alpelisib is an emerging challenge in breast cancer treatment. FGFR1 is frequently amplified in breast cancer. We investigated FGFR1 overexpression-mediated alpelisib resistance and its mechanism.

Methods: CCK-8, colony formation, and cell cycle assays assessed FGFR1 overexpression-induced alpelisib resistance in MCF-7 and T47D cells. FGFR1 siRNA knockdown validated FGFR1’s role. Akt, Erk, and ER signaling were analyzed by Western blot. Synergistic effects of alpelisib with AZD4547 and fulvestrant were evaluated using the combination index.

Results: FGFR1 overexpression conferred alpelisib resistance in MCF-7 and T47D cells, evidenced by increased viability, colony formation, and S-phase accumulation post alpelisib treatment. Knockdown of FGFR1 reverse alpelisib resistance in FGFR1 overexpressing MCF-7 and T47D cells. Resistance correlated with sustained activation of Akt and Erk1/2 pathways (p-Akt, p-Erk1/2, p-S6K, p-Rb) and attenuated suppression of ERα phosphorylation (S118/S167), highlighting RTK-ER crosstalk. Combining alpelisib with AZD4547 synergistically inhibited growth and suppressed both RTK signaling and ERα phosphorylation. While alpelisib-fulvestrant was effective, adding AZD4547 further enhanced inhibition, supporting triple therapy to overcome resistance.

Conclusion: Our findings establish FGFR1 as a key mediator of alpelisib resistance in ER+ breast cancer. Combining FGFR1 inhibitors with alpelisib-based therapies offers a viable approach for FGFR1-overexpressing tumors.

Cancers doi: 10.20517/cdr.2024.216

Authors: Jansen Redler, Ariana E. Nelson, Christine M. Heske

A common barrier to the development of effective anticancer agents is the development of drug resistance. This obstacle remains a challenge to successful clinical translation, particularly for targeted agents. Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors represent a clinically applicable drug class that exploits the increased dependence of cancer cells on nicotinamide adenine dinucleotide (NAD⁺), a coenzyme essential to metabolism and other cellular functions. NAMPT catalyzes the rate-limiting step in the NAD⁺ salvage pathway of mammalian cells and is overexpressed in numerous types of cancers. Preclinical research has demonstrated that pharmacological targeting of NAMPT may be an effective strategy against certain cancers, and while several early-phase clinical trials testing NAMPT inhibitors in refractory cancers have been completed, drug resistance is a concern. Preclinical work in a variety of cancer models has demonstrated the emergence of resistance to multiple NAMPT inhibitors through several recurrent mechanisms. This review represents the first article summarizing the current state of knowledge regarding the mechanisms of acquired drug resistance to NAMPT inhibitors with a particular focus on upregulation of the compensatory NAD⁺ production enzymes nicotinate phosphoribosyltransferase (NAPRT) and quinolinate phosphoribosyltransferase (QPRT), acquired mutations in NAMPT, metabolic reprogramming, and altered expression of the ATP-binding cassette (ABC) efflux transporter ABCB1. An understanding of how these mechanisms interact with the biology of each given cancer cell type to predispose to the acquisition of NAMPT inhibitor resistance will be necessary to develop strategies to optimize the use of these agents moving forward.

Cancers doi: 10.20517/cdr.2024.140

Authors: Qianyuan Li, Jie Cheng, Danni Qin, Sheng Xiao, Chenjiao Yao

Aim: Doxorubicin, pivotal for acute myeloid leukemia (AML) treatment, often succumbs to resistance, impeding therapeutic success. Although exosomal transfer is linked to chemoresistance, the detailed role of exosomal miRNAs in doxorubicin resistance remains incompletely understood.

Methods: We employed miRNA sequencing to delineate the profile of exosomal miRNAs in doxorubicin-resistant K562/DOX cells and AML patients. Subsequently, qPCR was utilized to scrutinize the expression of exosomal miR-92b-5p in these resistant cells and AML patients. A dual-luciferase reporter assay was conducted to elucidate the direct binding of miR-92b-5p to NEDD4 binding protein 1 (N4BP1). Furthermore, interactions between N4BP1 and NEDD4, as well as between NEDD4 and PTEN, were investigated by co-immunoprecipitation (Co-IP). Meanwhile, the ubiquitination of PTEN was also examined by Co-IP. Western blot analysis was applied to assess the expression levels of N4BP1, NEDD4, PTEN, RAD51, and proteins associated with the PI3K-AKT-mTOR pathway. Gain- and loss-of-function studies were conducted to ascertain the functional role of miR-92b-5p in doxorubicin resistance by using miR-92b-5p-mimic and miR-92b-5p-inhibitor transfections.

Results: Our study found exosomal miR-92b-5p was upregulated both in doxorubicin-resistant cells and AML patients. Moreover, miR-92b-5p targets N4BP1, promoting NEDD4-mediated mono-ubiquitination of PTEN. This alters PTEN’s subcellular localization, promoting nuclear PTEN and reducing cytoplasmic PTEN, which in turn leads to increased RAD51 for DNA repair and activation of the PI3K-AKT-mTOR pathway for cell proliferation, contributing to doxorubicin resistance.

Conclusion: Our study reveals a novel mechanism of doxorubicin resistance mediated by exosomal miR-92b-5p and provides potential therapeutic targets for overcoming drug resistance in AML.

Cancers doi: 10.20517/cdr.2024.195

Authors: Jinghan Hua, Zhe Wang, Xiaoxun Cheng, Jiaojiao Dai, Ping Zhao

Acquired drug resistance is a main factor contributing to cancer therapy failure and high cancer mortality, highlighting the necessity to develop novel intervention targets. Circular RNAs (circRNAs), an abundant class of RNA molecules with a closed loop structure, possess characteristics including high stability, which provide unique advantages in clinical application. Growing evidence indicates that aberrantly expressed circRNAs are associated with resistance against various cancer treatments, including targeted therapy, chemotherapy, radiotherapy, and immunotherapy. Therefore, targeting these aberrant circRNAs may offer a strategy to improve the efficiency of cancer therapy. Herein, we present a summary of the most recently studied circRNAs and their regulatory roles on cancer drug resistance. With the advances in artificial intelligence (AI)-based bioinformatics algorithms, circRNAs could emerge as promising biomarkers and intervention targets in cancer therapy.

Cancers doi: 10.20517/cdr.2024.213

Authors: Caterina Perfetto, Marianna Aprile, Simona Cataldi, Elisa Giovannetti, Valerio Costa

Aim: As intrinsic resistance - often driven by concurrent genomic alterations in tumor suppressor genes or oncogenes - remains a major challenge in oncology, this work aimed to comprehensively analyze BRAF somatic alterations across cancer types and identify new potential therapeutic strategies to overcome drug resistance.

Methods: We conducted an extensive analysis of genomics, transcriptomics, and clinical data retrieved from public repositories, including cBioPortal. Our comprehensive analysis examined BRAF alterations [point mutations, structural variants (SVs) and copy number alteration] in more than 217,000 tumor samples across 120 distinct tumor types from primary and metastatic sites in both adult and pediatric cohorts, focusing on mutual exclusivity and co-occurrence of mutations in other oncogenes or tumor suppressors. The work also explores the association of BRAF somatic alterations with survival, clinical and molecular features.

Results: Analysis of mutation frequencies across cancer types revealed that BRAFV600E represents approximately 90% of all BRAF alterations. While melanoma and thyroid carcinoma show the highest prevalence of BRAF mutations, followed by colorectal and non-small cell lung cancer in terms of absolute number of patients harboring BRAF mutations worldwide, notably high mutation frequencies were identified in rare malignancies, including hairy-cell leukemia, ganglioglioma, and serous borderline ovarian tumors. The comprehensive analysis of genomic profiling data across these tumors uncovered distinct patterns of co-occurring and mutually exclusive alterations in oncogenes and tumor suppressor genes, illuminating resistance mechanisms and suggesting novel therapeutic combinations.

Conclusion: Comprehensive genomic profiling is critical for optimizing targeted therapy and overcoming drug resistance in BRAF-mutated cancers. The identification of co-occurring alterations provides opportunities for rational combination therapies, emphasizing the importance of detailed mutation profiling in developing effective treatment strategies across diverse cancer types.

Cancers doi: 10.20517/cdr.2024.178

Authors: Chi Teng, Jia-Wen Chen, Li-Sha Shen, Sibao Chen, Guo-Qing Chen

Cancer remains a significant global health challenge, with current chemotherapeutic strategies frequently limited by the emergence of resistance. In this context, natural compounds with the potential to overcome resistance have garnered considerable attention. Among these, sesquiterpene lactones, primarily derived from plants in the Asteraceae family, stand out for their potential anticancer properties. This review specifically focuses on five key signaling pathways: PI3K/Akt/mTOR, NF-κB, Wnt/β-catenin, MAPK/ERK, and STAT3, which play central roles in the mechanisms of cancer resistance. For each of these pathways, we detail their involvement in both cancer development and the emergence of drug resistance. Additionally, we investigate how sesquiterpene lactones modulate these pathways to overcome resistance across diverse cancer types. These insights highlight the potential of sesquiterpene lactones to drive the advancement of novel therapies that can effectively combat both cancer progression and drug resistance.

Cancers doi: 10.20517/cdr.2024.157

Authors: Aanya Shahani, Hasan Slika, Ahmad Elbeltagy, Alexandra Lee, Christopher Peters, Toriyn Dotson, Divyaansh Raj, Betty Tyler

Glioblastoma (GBM) is an aggressive malignant brain tumor with almost inevitable recurrence despite multimodal management with surgical resection and radio-chemotherapy. While several genetic, proteomic, cellular, and anatomic factors interplay to drive recurrence and promote treatment resistance, the epigenetic component remains among the most versatile and heterogeneous of these factors. Herein, the epigenetic landscape of GBM refers to a myriad of modifications and processes that can alter gene expression without altering the genetic code of cancer cells. These processes encompass DNA methylation, histone modification, chromatin remodeling, and non-coding RNA molecules, all of which have been found to be implicated in augmenting the tumor’s aggressive behavior and driving its resistance to therapeutics. This review aims to delve into the underlying interactions that mediate this role for each of these epigenetic components. Further, it discusses the two-way relationship between epigenetic modifications and tumor heterogeneity and plasticity, which are crucial to effectively treat GBM. Finally, we build on the previous characterization of epigenetic modifications and interactions to explore specific targets that have been investigated for the development of promising therapeutic agents.

Cancers doi: 10.20517/cdr.2024.180

Authors: Émilie Audrey Larose, Xinying Hua, Silin Yu, Amritha Thulaseedharan Pillai, Zongbi Yi, Haijun Yu

Antibody-drug conjugates (ADCs) are a transformative approach in breast cancer therapy, offering targeted treatment with reduced toxicity by selectively delivering cytotoxic agents to cancer cells. While ADCs like trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan have shown significant efficacy, resistance mechanisms such as antigen loss, impaired internalization, and efflux of cytotoxic payloads challenge their effectiveness. This review discusses these resistance mechanisms and explores advanced strategies to overcome them, including innovations in linker chemistry, multi-antigen targeting, and biomarker-driven personalization. Additionally, therapeutic sequencing - determining the optimal order of ADCs with other treatments such as chemotherapy, endocrine therapy, and immunotherapy - is examined as a crucial approach to maximize ADC efficacy and manage resistance. Evidence-based sequencing strategies, particularly for human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC), are supported by clinical trials demonstrating the benefits of ADCs in both early-stage and metastatic settings. The potential of combination therapies, such as ADCs with immune checkpoint inhibitors (ICIs), further highlights the evolving landscape of breast cancer treatment. As ADC technology advances, personalized approaches integrating biomarkers and optimized sequencing protocols offer promising avenues to enhance treatment outcomes and combat resistance in breast cancer.

Cancers doi: 10.20517/cdr.2024.165

Authors: Yi-Zhe Zhang, Yunshu Ma, Ensi Ma, Xizhi Chen, Yue Zhang, Baobing Yin, Jing Zhao

Hepatocellular carcinoma (HCC) remains a serious threat to global health, with rising incidence and mortality rates. Therapeutic options for advanced HCC are quite limited, and the overall prognosis remains poor. Recent advancements in immunotherapy, particularly immune-checkpoint blockade (ICB) targeting anti-PD1/PD-L1 and anti-CTLA4, have facilitated a paradigm shift in cancer treatment, demonstrating substantial survival benefits across various cancer types, including HCC. However, only a subset of HCC patients exhibit a favorable response to ICB therapy, and its efficacy is often hindered by the development of resistance. There are many studies to explore the underlying mechanisms of ICB response. In this review, we compiled the latest progression in immunotherapies for HCC and systematically summarized the sophisticated mechanisms by which components of the tumor microenvironment (TME) regulate resistance to ICB therapy. Additionally, we also outlined some scientific rationale strategies to boost antitumor immunity and enhance the efficacy of ICB in HCC. These insights may serve as a roadmap for future research and help improve outcomes for HCC patients.

Cancers doi: 10.20517/cdr.2024.173

Authors: Adam Khorasanchi, Feng Hong, Yuanquan Yang, Eric A. Singer, Peng Wang, Mingjia Li, Linghua Zheng, Paul Monk, Amir Mortazavi, Lingbin Meng

Metastatic castration-resistant prostate cancer (mCRPC) is driven by a complex network of resistance mechanisms against standard-of-care therapies, resulting in poor long-term outcomes. This review offers a uniquely comprehensive and integrative perspective on these resistance pathways, systematically examining both androgen receptor (AR)-dependent factors (including AR overexpression, point mutations, glucocorticoid receptor signaling, splice variants, post-translational modifications, altered coregulators, and intratumoral hormone biosynthesis) and AR-independent pathways (such as neuroendocrine differentiation, lineage plasticity, and alternative growth factor signaling). We also highlight resistance mechanisms influencing immunotherapy, chemotherapy, radiopharmaceutical therapy and targeted therapy. By synthesizing emerging insights across these domains, this review not only clarifies the underlying biology of mCRPC resistance but also identifies key leverage points for more effective interventions. Building on this foundation, we propose a forward-looking framework for overcoming mCRPC drug resistance, emphasizing the importance of biomarker-guided patient selection, combination strategies that simultaneously target multiple resistance mechanisms, and novel therapies under investigation. These recommendations are intended to guide future clinical trial designs and research priorities that move beyond incremental improvements. Ultimately, this comprehensive synthesis aims to serve as a resource for clinicians and researchers to accelerate the development of durable, precision-based treatment strategies in mCRPC.

Cancers doi: 10.20517/cdr.2024.177

Authors: Yu-Qing Chen, Jia-Xiong Tan, Ling-Ling Gao, Jia-Xing Yang, Jie Huang, Jin-Ji Yang, Qiang Zhao

Aim: Small-cell lung cancer (SCLC) is usually diagnosed as an advanced stage with a poor outcome. SCLC has limited response to immunotherapy due to the absence or lack of immune cell infiltration, so studying its tumor immune microenvironment (TIME) is essential.

Methods: The study involved patients with extensive-stage small-cell lung cancer (ES-SCLC) diagnosed at the Guangdong Lung Cancer Institute between January 2018 and April 2022 who had received the atezolizumab/carboplatin/etoposide (ECT) treatment. We used multi-immunohistochemistry (mIHC) to assess the prognostic value of YAP1 and TIME in SCLC, with results confirmed using public data.

Results: 15 patients with sufficient baseline biopsy samples were included in this study. The total population of YAP1-positive cells is inversely related to progression-free survival (PFS) and shows a potential negative correlation with overall survival (OS). CD56-positive cells are the primary components of TIME in SCLC tumor parenchyma and stroma. The total population and cell density of YAP1-positive cells are significantly positively correlated with CD4-positive cells. Furthermore, in the tumor parenchyma, both the proportion and the cell density of YAP1-positive cells are positively correlated with that of FOXP3-positive cells. The total population of CD56-positive cells showed a negative correlation trend with YAP1-positive cells but without significant difference.

Conclusion: YAP1 has shown prognostic value in SCLC patients receiving ECT regimen treatment. The high expression level of YAP1 seems related to the inhibitory TIME. However, some prospective studies with larger populations are warranted.

Cancers doi: 10.20517/cdr.2024.164

Authors: Chahat Suri, Babita Pande, Lakkakula Suhasini Sahithi, Shashikant Swarnkar, Tuneer Khelkar, Henu Kumar Verma

Metabolic reprogramming within the tumor microenvironment (TME) plays a critical role in driving drug resistance in gastrointestinal cancers (GI), particularly through the pathways of fatty acid oxidation and glycolysis. Cancer cells often rewire their metabolism to sustain growth and reshape the TME, creating conditions such as nutrient depletion, hypoxia, and acidity that impair antitumor immune responses. Immune cells within the TME also undergo metabolic alterations, frequently adopting immunosuppressive phenotypes that promote tumor progression and reduce the efficacy of therapies. The competition for essential nutrients, particularly glucose, between cancer and immune cells compromises the antitumor functions of effector immune cells, such as T cells. Additionally, metabolic by-products like lactate and kynurenine further suppress immune activity and promote immunosuppressive populations, including regulatory T cells and M2 macrophages. Targeting metabolic pathways such as fatty acid oxidation and glycolysis presents new opportunities to overcome drug resistance and improve therapeutic outcomes in GI cancers. Modulating these key pathways has the potential to reinvigorate exhausted immune cells, shift immunosuppressive cells toward antitumor phenotypes, and enhance the effectiveness of immunotherapies and other treatments. Future strategies will require continued research into TME metabolism, the development of novel metabolic inhibitors, and clinical trials evaluating combination therapies. Identifying and validating metabolic biomarkers will also be crucial for patient stratification and treatment monitoring. Insights into metabolic reprogramming in GI cancers may have broader implications across multiple cancer types, offering new avenues for improving cancer treatment.

Cancers doi: 10.20517/cdr.2024.125

Authors: Bernhard Biersack, Bianca Nitzsche, Michael Höpfner

Small-molecule BRAF inhibitors (e.g., vemurafenib and dabrafenib) and MEK (MAPK/ERK) kinases inhibitors (e.g., trametinib) have distinctly improved the survival of patients suffering from BRAF-mutant cancers such as melanomas. However, the emergence of resistance to BRAF and MEK inhibitor-based melanoma therapy, as well as the reduced sensitivity of other BRAF-mutant cancers such as CRC, poses a considerable clinical problem. For instance, the reactivation of MAPK/ERK signaling hampering cell death induction mechanisms was responsible for BRAF inhibitor resistance, which can be correlated with distinct post-translational and epigenetic processes. Histone deacetylases (HDACs) are prominent epigenetic drug targets and some HDAC inhibitors have already been clinically approved for the therapy of various blood cancers. In addition, several HDACs were identified, which also play a crucial role in the drug resistance of BRAF-mutant cancers. Consequently, inhibition of HDACs was described as a promising approach to overcome resistance. This review summarizes the influence of HDACs (Zn²⁺-dependent HDACs and NAD⁺-dependent sirtuins) on BRAF-mutant cancers and BRAF inhibitor resistance based on upregulated survival mechanisms and the prevention of tumor cell death. Moreover, it outlines reasonable HDAC-based strategies to circumvent BRAF-associated resistance mechanisms based on downregulated cell death mechanisms.

Cancers doi: 10.20517/cdr.2024.169

Authors: Juan Miguel Cejalvo Andújar, Francisco Ayala de la Peña, Mireia Margeli Vila, Javier Pascual, Pablo Tolosa, Cristina Pages, Mónica Cuenca, Ángel Guerrero Zotano

This review offers an expert perspective on biomarkers, CDK4/6 inhibitor efficacy, and therapeutic approaches for managing hormone receptor-positive (HR+), human epidermal growth factor receptor-negative (HER2-) advanced breast cancer (ABC), particularly after CDK4/6 inhibitor progression. Key trials have demonstrated that combining CDK4/6 inhibitors with endocrine therapy (ET) significantly improves progression-free survival (PFS), with median durations ranging from 14.8 to 26.7 months, and overall survival (OS), with median durations reaching up to 53.7 months. Actionable biomarkers, such as PIK3CA and ESR1 mutations, have emerged as pivotal tools to guide second-line treatment decisions, enabling the use of targeted therapies like alpelisib and elacestrant and emphasizing the important role of biomarkers in guiding the selection of therapy. This overview aims to provide clinicians with a practical and up-to-date framework to inform treatment decisions and improve patient care in the context of this challenging disease. Additionally, we review emerging biomarkers and novel treatment strategies to address this difficult clinical landscape.

Cancers doi: 10.20517/cdr.2024.167

Authors: Heng Zhang, Hailin Tang, Wenling Tu, Fu Peng

Gastrointestinal (GI) cancers are becoming a growing cause of morbidity and mortality globally, posing a significant risk to human life and health. The main treatment for this kind of cancer is chemotherapy based on 5-fluorouracil (5-FU). However, the issue of 5-FU resistance is becoming increasingly prominent, which greatly limits its effectiveness in clinical treatment. Recently, numerous studies have disclosed that some non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), exert remarkable physiological functions within cells. In addition, these ncRNAs can also serve as important information communication molecules in the tumor microenvironment and regulate tumor chemotherapy resistance. In particular, they have been shown to play multiple roles in regulating 5-FU resistance in GI cancers. Herein, we summarize the targets, pathways, and mechanisms involved in regulating 5-FU resistance by ncRNAs and briefly discuss the application potential of ncRNAs as biomarkers or therapeutic targets for 5-FU resistance in GI cancers, aiming to offer a reference to tackle issues related to 5-FU resistance.

Cancers doi: 10.20517/cdr.2024.91

Authors: Zilu Chen, Kun Mei, Foxing Tan, Yuheng Zhou, Haolin Du, Min Wang, Renjun Gu, Yan Huang

Aim: Lung adenocarcinoma (LUAD), the most prevalent subtype of non-small cell lung cancer (NSCLC), presents significant clinical challenges due to its high mortality and limited therapeutic options. The molecular heterogeneity and the development of therapeutic resistance further complicate treatment, underscoring the need for a more comprehensive understanding of its cellular and molecular characteristics. This study sought to delineate novel cellular subpopulations and molecular subtypes of LUAD, identify critical biomarkers, and explore potential therapeutic targets to enhance treatment efficacy and patient prognosis.

Methods: An integrative multi-omics approach was employed to incorporate single-cell RNA sequencing (scRNA-seq), bulk transcriptomic analysis, and genome-wide association study (GWAS) data from multiple LUAD patient cohorts. Advanced computational approaches, including Bayesian deconvolution and machine learning algorithms, were used to comprehensively characterize the tumor microenvironment, classify LUAD subtypes, and develop a robust prognostic model.

Results: Our analysis identified eleven distinct cellular subpopulations within LUAD, with epithelial cells predominating and exhibiting high mutation frequencies in Tumor Protein 53 (TP53) and Titin (TTN) genes. Two molecular subtypes of LUAD [consensus subtype (CS)1 and CS2] were identified, each showing distinct immune landscapes and clinical outcomes. The CS2 subtype, characterized by increased immune cell infiltration, demonstrated a more favorable prognosis and higher sensitivity to immunotherapy. Furthermore, a multi-omics-driven machine learning signature (MOMLS) identified ribonucleotide reductase M1 (RRM1) as a critical biomarker associated with chemotherapy response. Based on this model, several potential therapeutic agents targeting different subtypes were proposed.

Conclusion: This study presents a comprehensive multi-omics framework for understanding the molecular complexity of LUAD, providing insights into cellular heterogeneity, molecular subtypes, and potential therapeutic targets. Differential sensitivity to immunotherapy among various cellular subpopulations was identified, paving the way for future immunotherapy-focused research.

Cancers doi: 10.20517/cdr.2024.152

Authors: Jindong Xie, Xinmei Lin, Xinpei Deng, Hailin Tang, Yutian Zou, Wenkuan Chen, Xiaoming Xie

Cancer-associated fibroblasts (CAFs) constitute a critical component of the tumor microenvironment (TME). CAFs can be reprogrammed by cancer cells, leading to the production of extracellular vesicles (EVs). These EVs serve as carriers for bioactive substances, including proteins, nucleic acids, and metabolic products, thereby facilitating tumor progression. CAF-derived EVs exert substantial influence on tumor cell proliferation, invasion, and metastasis, the immunological environment, and the processes of lymphangiogenesis and angiogenesis. Despite their potential as non-invasive biomarkers and therapeutic delivery vehicles, the clinical application of CAF-derived EVs is currently limited by challenges in purification and precise targeting. This review delineates the diverse roles of CAF-derived EVs in tumor growth, metastasis, and immune evasion within the TME.

Cancers doi: 10.20517/cdr.2024.151

Authors: Yang Yang, Simin Yu, Wanyao Liu, Yi Zhuo, Chunrun Qu, Yu Zeng

Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation. This process is regulated by signaling pathways associated with redox balance, iron metabolism, and lipid metabolism. Cancer cells’ increased iron demand makes them especially susceptible to ferroptosis, significantly influencing cancer development, therapeutic response, and metastasis. Recent findings indicate that cancer cells can evade ferroptosis by downregulating key signaling pathways related to this process, contributing to drug resistance. This underscores the possibility of modulating ferroptosis as an approach to counteract drug resistance and enhance therapeutic efficacy. This review outlines the signaling pathways involved in ferroptosis and their interactions with cancer-related signaling pathways. We also highlight the current understanding of ferroptosis in cancer drug resistance, offering insights into how targeting ferroptosis can provide novel therapeutic approaches for drug-resistant cancers. Finally, we explore the potential of ferroptosis-inducing compounds and examine the challenges and opportunities for drug development in this evolving field.

Cancers doi: 10.20517/cdr.2025.110

Authors: Zhuoqing Xu,Silei Sun,Han Gao,Runhua Feng,Xiaohui Shen

Aim: Patients with KRAS-mutated colorectal cancer (CRC) frequently exhibit resistance to conventional chemotherapy and epidermal growth factor receptor (EGFR)-targeted therapies. This study investigates the role of the transcription factor KLF5 in mediating proliferation and chemoresistance in KRAS-mutated CRC, aiming to identify novel therapeutic strategies to improve treatment outcomes.

Methods: We analyzed the association between KLF5 expression, KRAS mutation status, and patient prognosis using CRC tissue microarrays and public datasets. Proliferative capacity and oxaliplatin sensitivity were compared between KRAS-mutated and wild-type patient-derived organoids. RNA sequencing and CUT&Tag sequencing were employed to assess KLF5-mediated chromatin accessibility and downstream transcriptional regulation in KRAS-mutated CRC cells. In vitro and in vivo functional studies were conducted using three pairs of KRAS-mutated CRC cell lines (with KLF5 knockdown or overexpression) to evaluate KLF5’s impact on proliferation, cell cycle progression, stemness, and oxaliplatin response.

Results: KRAS-mutated CRC demonstrated enhanced proliferative capacity and oxaliplatin resistance, accompanied by KLF5 upregulation. In KRAS-mutated CRC cells, KLF5 promoted chromatin accessibility to initiate downstream transcription programs regulating cell cycle progression, platinum drug resistance, and apoptosis. Mechanistically, KLF5 drives oxaliplatin resistance by promoting proliferation through upregulation of the CDK4/6-Cyclin D1 axis, enhancing stemness via LGR5 and Nanog, and activating the XIAP/Bcl-2-dependent anti-apoptotic signaling pathway. In vivo experiments further confirmed that KLF5-overexpressing KRAS-mutated CRC tumors exhibited accelerated growth and reduced oxaliplatin sensitivity.

Conclusion: This study reveals that aberrantly elevated KLF5 promotes proliferation and chemoresistance in KRAS-mutated CRC. Targeting KLF5 represents a promising strategy to enhance chemotherapeutic response in this aggressive CRC subtype, offering a rationale for clinical translation.

Cancers doi: 10.20517/cdr.2025.119

Authors: Cheng Hu,Song Wei,Wenbo Zhu,Boran Lv,Shuhao Li,Baiyu Liu,Guangmei Yan,Ying Liu

Aim: Muscle-invasive bladder cancer (MIBC) remains lethal despite promising oncolytic virotherapy, hindered by tumor-intrinsic resistance. This study aimed to elucidate the molecular basis underlying differential sensitivity to the oncolytic M1 virus in bladder cancer.

Methods: Bladder cancer cell lines with varying sensitivity to M1 were analyzed for endoplasmic reticulum (ER) stress responses and unfolded protein response (UPR) pathway activation. IRE1α expression was modulated using small interfering RNA and a selective inhibitor. Viral cytotoxicity, replication, and apoptosis were assessed using viability assays, immunofluorescence, electron microscopy, and immunoblotting. In vivo antitumor efficacy was assessed using xenografted mice. Clinical relevance was examined using patient-derived cells and survival data from The Cancer Genome Atlas.

Results: M1 virus induced ER stress and apoptosis in sensitive cells (e.g., T24, UM-UC-3) supporting viral protein expression, whereas low-sensitivity cells like EJ showed minimal response due to limited viral replication. In moderately sensitive cells, M1 replication led to viral protein accumulation, triggering IRE1α upregulation, which in turn limited further protein buildup and apoptosis. IRE1α inhibition enhanced M1-induced ER stress, apoptotic signaling, and oncolysis without affecting viral replication capacity. In vivo, M1 plus STF083010 achieved greater tumor suppression than monotherapy without added toxicity. Analysis of patient-derived cells and TCGA data further revealed downregulation of IRE1α in primary tumors and its potential association with worse prognosis.

Conclusion: IRE1α modulates M1-induced viral protein accumulation and cell death. Inhibiting IRE1α enhances ER stress and potentiates the oncolytic effect of M1 virus. Targeting IRE1α may improve M1-based virotherapy outcomes in accessible tumors.

Cancers doi: 10.20517/cdr.2025.38

Authors: Jiangning Gu,Zihao Dai,Tianci Shen,Xiang Chen,Zhuo Yang,Shibo Sun,Dan Chen,Haifeng Luo,Xiuli Wang,Jianqiang Xu

Aim: Cyclin-dependent kinases 4 and 6 (CDK4/6) are frequently upregulated in pancreatic ductal adenocarcinoma (PDAC) and are associated with poor overall survival. Although CDK4/6 inhibition suppresses tumor cell proliferation, it paradoxically promotes metastasis and invasion, and the mechanisms underlying this effect remain unclear.

Methods: We evaluated the effects of the CDK4/6 inhibitor palbociclib (PD-0332991) and the bromodomain and extra-terminal (BET) inhibitor JQ1, administered individually and in combination, on human PDAC cell lines in vitro and on tumor growth in an orthotopic mouse model.

Results: Palbociclib modestly inhibited pancreatic tumor growth but significantly enhanced tumor cell migration, invasion, and epithelial-to-mesenchymal transition (EMT). In contrast, co-treatment with JQ1 potentiated palbociclib’s anti-proliferative effects and reversed EMT. Mechanistically, CDK4/6 inhibition activated the canonical Wnt/β-catenin pathway via Ser9 phosphorylation of GSK3β, whereas BET inhibition disrupted the cross-talk between Wnt/β-catenin and TGF-β/Smad signaling. Combined inhibition of CDK4/6 and BET produced a synergistic antitumor effect in vitro and in vivo.

Conclusion: Our findings support a combined therapeutic strategy targeting CDK4/6 and BET proteins to achieve synergistic inhibition of PDAC progression.

Cancers doi: 10.20517/cdr.2025.107

Authors: Ketaki Sandu,Rolf Warta,Uddipta Biswas,Wang Zhang,Patrick Michl,Christel Herold-Mende,Johanna Weiss,Dirk Theile

Aim: Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) is thought to involve both reduced drug uptake and altered molecular responses. However, the relative contribution of these mechanisms remains unclear.

Methods: Two HNSCC cell lines with differing sensitivity (HNO97 and HNO41) were analyzed using cytotoxicity assays, atomic absorption spectroscopy-based quantification of intracellular cisplatin, caspase 3/7 assays, Western blotting, polymerase chain reaction (PCR)-based transcriptomic analysis of DNA damage response and cell cycle arrest pathways, and RNA-seq data from The Cancer Genome Atlas (TCGA) to characterize the resistance phenotype.

Results: HNO97 (IC₅₀ = 440 µM) was 7.6-fold more resistant to cisplatin than HNO41 (IC₅₀ = 57.8 µM; P = 0.0286). After quantifying intracellular uptake (pg Pt/µg protein) and normalizing cytotoxicity to intracellular drug levels, HNO97 (IC₅₀ = 778.9 pg Pt/µg protein) remained 5-fold more resistant than HNO41 (IC₅₀ = 153.5 pg Pt/µg protein), indicating only a partial reduction in resistance (33% decrease, from 7.6-fold to 5-fold; P = 0.0286). At cisplatin concentrations yielding comparable intracellular exposure (HNO97: 440 µM; HNO41: 196 µM; both ≈ 725 pg Pt/µg protein), caspase 3/7 activation and induction of CDKN1A, GADD45A, GADD45G, and PPP1R15A were weaker in HNO97 than in HNO41. Notably, baseline expression of these genes was significantly higher in HNO97. In the TCGA cohort, multivariate analysis showed that high FANCD2 expression was associated with unfavorable recurrence-free survival in platinum-treated patients (hazard ratio = 4.0; P = 0.011), but not in those who did not receive platinum chemotherapy.

Conclusion: Cisplatin resistance in HNSCC appears to be driven primarily by molecular mechanisms involving DNA damage response and cell cycle arrest pathways, rather than poor drug uptake.

Cancers doi: 10.20517/cdr.2025.88

Authors: Cristina Corno,Debora Russo,Francesco Pignotti,Francesca De Giorgi,Ilaria Penna,Francesco Saccoliti,Matteo Costantino,Luca Mirra,Pietro Pettinari,Nives Carenini,Elisabetta Corna,Nunzio Perta,Chiara M Ciniselli,Pietro Pratesi,Rita Scarpelli,Fabio Bertozzi,Paolo Verderio,Giovanni L. Beretta,Giovanni Di Muccio,Daniele Di Marino,Tiziano Bandiera,Paola Perego

Aim: This study aims to investigate the biological role of the proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14) in ovarian carcinoma drug resistance and to identify novel USP14 inhibitors (USP14i) for further preclinical development.

Methods: USP14 expression was evaluated in clinical samples from 134 ovarian carcinoma patients and in a broad panel of human ovarian carcinoma cell lines. Functional studies, including gain- and loss-of-function assays, migration and invasion, and apoptosis induction assays, were conducted using cisplatin-sensitive IGROV-1 cells and their cisplatin-resistant derivative IGROV-1/Pt1. A library of 1,056 small molecules was screened using an optimized hydrolysis assay. Docking and molecular dynamics simulations were employed to predict binding modes of candidate inhibitors within the USP14 domain.

Results: In clinical specimens, USP14 mRNA expression was associated with tumor grade. Exogenous overexpression of USP14 enhanced the survival of cisplatin-resistant IGROV-1/Pt1 cells, but not parental IGROV-1 cells, upon cisplatin exposure. USP14 knockdown by small interfering RNAs in resistant cells reduced aggressive features and restored cisplatin sensitivity, whereas no sensitization was observed in IGROV-1 cells. Medium-throughput screening identified five candidate molecules, among which ARN12502 showed the strongest inhibitory activity against USP14. ARN12502 exhibited an IC₅₀ of 18.4 µM, and molecular dynamics simulations confirmed stable binding in two distinct modes. In proteasome sensor-expressing cells, ARN12502 displayed proteasome-inhibitory activity.

Conclusion: USP14 contributes to the aggressiveness of ovarian carcinoma, particularly to the cisplatin-resistant phenotype, and represents a relevant promising druggable target. ARN12502 serves as a starting point for chemical optimization toward the development of more potent USP14i.

Cancers doi: 10.20517/cdr.2025.95

Authors: Monika Cuprych-Belter,Agnieszka Łupicka-Słowik,Artur Anisiewicz,Martin Michaelis,Jindrich Cinatl Jr.,Mateusz Psurski

Aim: Urinary bladder cancer (UBC) often develops chemoresistance, reducing treatment effectiveness. This study aimed to investigate diverse molecular mechanisms underlying acquired resistance by establishing and characterizing a comprehensive panel of UBC cell lines resistant to common chemotherapeutics.

Methods: Fifteen UBC cell lines were examined: three parental lines (RT-112, TCC-SUP, UMUC-3) and twelve derived sublines adapted to cisplatin, vinblastine, or gemcitabine. Drug sensitivity was assessed using the SRB assay. Resistance mechanisms were explored via quantitative real-time PCR (targeting genes including ABCB1, dCK, hENT1, ECHDC1, TUBB3), Western blotting (assessing proteins such as p21, Cyclin B, and Mcl-1), and biochemical assessment of glutathione levels and redox state.

Results: The adapted sublines exhibited distinct resistance profiles and cross-resistance patterns. Gene expression and protein analyses revealed drug- and lineage-specific alterations, involving factors such as p21, Cyclin B, and Mcl-1. Changes in glutathione metabolism were also associated with resistance. Notably, no single, universal mechanism accounted for resistance across the entire panel.

Conclusion: UBC cells develop diverse, context-dependent adaptive strategies to resist cisplatin, vinblastine, and gemcitabine. These findings highlight the complexity of chemoresistance mechanisms. The characterized cell line panel represents a valuable resource for future studies aimed at understanding and overcoming drug resistance in bladder cancer, suggesting that personalized therapeutic approaches may be necessary.

Cancers doi: 10.20517/cdr.2025.133

Authors: Shuangshuang Lu,Yuliang Zhang,Yiwei Tong,Lan Shu,Renhong Huang,Yijin Gu,Chaofu Wang,Jianfeng Li,Kunwei Shen,Lei Dong,Xiaosong Chen

Aim: Resistance to trastuzumab remains a major barrier to cure in early-stage HER2-positive breast cancer (HER2+ BC). We investigated the impact of genomic alterations and tumor-infiltrating lymphocyte (TIL) density on treatment resistance and survival outcomes.

Methods: We retrospectively analyzed 315 patients with HER2+ BC who received adjuvant trastuzumab at Ruijin Hospital (2009-2019). Whole-exome sequencing and TIL scoring were performed on surgical specimens, and clinical and pathological data were collected. The Cancer Genome Atlas (TCGA) cohort was used for external validation. Genomic alterations and TIL density were compared between trastuzumab-sensitive and -resistant tumors. Survival analyses were conducted to identify prognostic biomarkers.

Results: After a median follow-up of 109.3 months, 67 tumors (21.3%) were trastuzumab-resistant, exhibiting lower TIL density (mean 19.8% vs. 26.3%, P = 0.001), higher mutation frequencies in FLG, MAP1A, BRCA1, PTPRD, PAPPA2, NCOR2, FBXW7, MYH7, and VCAN, and more frequent alterations in the TP53/NOTCH pathways compared with sensitive tumors (all P < 0.05). A 15-gene trastuzumab response-associated gene (TRAG) signature independently predicted poorer disease-free survival (DFS) in both our cohort (HR, 3.57, P < 0.001) and the TCGA cohort (HR, 4.99, P = 0.037). A high copy number alteration burden was associated with worse overall survival (HR, 2.49, P = 0.043), whereas TIL density > 10% was associated with improved DFS (HR, 2.44, P = 0.003). A prognostic model integrating tumor size, nodal status, estrogen receptor status, TILs, and the TRAG signature showed strong discriminatory power (c-index 0.743 in the training set; 0.915 in the validation set).

Conclusion: Genomic alterations and reduced TIL density underpin trastuzumab resistance. The novel TRAG signature and integrated prognostic model enhance risk stratification and may guide personalized adjuvant therapy in early-stage HER2+ BC.

Cancers doi: 10.20517/cdr.2025.132

Authors: Xiaoliang Cheng,Peixing Wang,Hongqiang Lyu,Yonghyun Lee,Juyoung Yoon,Haiyan Dong

Immunotherapy has emerged as a major therapeutic strategy for cancer; however, immunotherapy resistance remains a significant challenge. Hypoxia, a key hallmark of the tumor microenvironment resulting from the imbalance between the high oxygen demand of rapidly proliferating cancer cells and the limited supply from abnormal blood vessels, plays a central role in driving immunotherapy resistance. Hypoxia-inducible factor-1α (HIF-1α) and its downstream signaling pathways contribute to this resistance by promoting macrophage polarization toward the protumorigenic M2 phenotype, inducing T cell exhaustion, facilitating immune evasion, enhancing angiogenesis, and activating other resistance mechanisms. The review highlights the mechanisms by which hypoxia regulates resistance to immunotherapy and provides a comprehensive overview of nanotechnology-based strategies designed to counteract hypoxia-induced resistance. Finally, the prospects and challenges of translating nanomedicine-based drug delivery systems into clinical practice for overcoming immunotherapy resistance are outlined.

Cancers doi: 10.20517/cdr.2025.103

Authors: Fangquan Chen,Junhao Lin,Xiutao Cai,Hu Tang,Shengfeng Li,Ruirui Liang,Rui Kang,Zhenhui Zhang,Daolin Tang,Jiao Liu

Aim: Dysregulation of tumor-suppressive pathways can lead to constitutive activation of multiple oncogenic signaling cascades. Such overactivation makes cancer cells highly dependent on these pathways, creating potential therapeutic vulnerabilities. Based on our previous findings and current data, genetic knockout of ATPase H⁺ transporting V0 subunit D1 (ATP6V0D1) - a key mediator of alkaliptosis - induces hyperactivation of oncogenic pathways, including signal transducer and activator of transcription 3 (STAT3)-mediated lysosomal pH regulation and AKT serine/threonine kinase (AKT) signaling. It also alters cellular responses to cryptotanshinone therapy. This study aimed to investigate how ATP6V0D1 deficiency reshapes oncogenic signaling networks and cellular heterogeneity in pancreatic ductal adenocarcinoma (PDAC), while evaluating therapeutic strategies that exploit alkaliptosis-related vulnerabilities.

Methods: ATP6V0D1-deficient SW1990 and MIAPaCa2 cells were generated via gene knockdown. Cell viability and death following various treatments were assessed using CCK-8 and propidium iodide assays. Transcriptomic analysis was conducted to identify feedback signaling pathways, while Western blotting was used to measure expression of signaling proteins. Macropinocytosis was evaluated by TRITC-dextran uptake. Additionally, The Cancer Dependency Map (DepMap) database was analyzed to explore background differences between SW1990 and MIAPaCa2 cells.

Results: ATP6V0D1 deletion led to overactivation of STAT3-mediated lysosomal pH regulation and AKT signaling; inhibition of these pathways restored alkaliptosis. Notably, cryptotanshinone selectively induced cell death in ATP6V0D1-deficient MIAPaCa2 cells but not SW1990 cells. Resistance in SW1990 cells was mediated by FGFR2 upregulation, which was reversed upon FGFR2 inhibition.

Conclusion: ATP6V0D1 deficiency drives PDAC progression via dual mechanisms: compensatory oncogenic signaling (STAT3/AKT) and FGFR2-mediated cellular heterogeneity. While targeting these pathways may offer therapeutic potential, tumor heterogeneity remains a major clinical challenge.

Cancers doi: 10.20517/cdr.2025.112

Authors: Cole Ruoff,Allison Mitchell,Priya Mondal,Vishaka Gopalan,Arashdeep Singh,Michael Gottesman,Sridhar Hannenhalli

Aim: Growing evidence points to non-genetic mechanisms underlying long-term resistance to cancer therapies. These mechanisms involve pre-existing or therapy-induced transcriptional cell states that confer resistance. However, the relationship between early transcriptional responses to treatment and the eventual emergence of resistant states remains poorly understood. Furthermore, it is unclear whether such early resistance-associated transcriptional responses are evolutionarily conserved. In this study, we examine the similarity between early transcriptional responses and long-term resistant states, assess their clinical relevance, and explore their evolutionary conservation across species.

Methods: We integrated datasets on early drug responses and long-term resistance from multiple cancer cell lines, bacteria, and yeast to identify early transcriptional changes predictive of long-term resistance and assess their evolutionary conservation. Using genome-wide CRISPR-Cas9 knockout screens, we evaluated the impact of genes associated with resistant transcriptional states on drug sensitivity. Clinical datasets were analyzed to explore the prognostic value of the identified resistance-associated gene signatures.

Results: We found that transcriptional states observed in drug-naive cells and shortly after treatment overlapped with those seen in fully resistant populations. Some of these shared features appear to be evolutionarily conserved. Knockout of genes marking resistant states sensitized ovarian cancer cells to Prexasertib. Moreover, early resistance gene signatures effectively distinguished therapy responders from non-responders in multiple clinical cancer trials and differentiated premalignant breast lesions that progressed to malignancy from those that remained benign.

Conclusion: Early cellular transcriptional responses to therapy exhibit key similarities to fully resistant states across different drugs, cancer types, and species. Gene signatures defining these early resistance states have prognostic value in clinical settings.

Cancers doi: 10.20517/cdr.2025.122

Authors: Mengle Long,Shixuan Peng,Qingyang Wen,Zhijian Yin,Xinwen Zhang,Haoyu Tan,Yun Xu,Yongjun Wu

Despite the development of various effective anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), therapeutic resistance remains a major challenge. Both on-target and off-target mechanisms have been identified as key contributors to resistance. With the popularization of genetic testing and the development of precision therapies, the prognosis and survival of patients with ALK-positive non-small cell lung cancer (NSCLC) have improved. However, even with second- and third-generation ALK-TKIs, overcoming resistance remains difficult. Resistance frequently arises during approved treatments, underscoring the need for further research to elucidate the molecular events and resistance mechanisms associated with ALK-positive lung cancer. The discovery of anaplastic lymphoma kinase (ALK) rearrangement as an actionable oncogenic driver in NSCLC has established a biomarker-driven treatment paradigm for advanced disease. This article summarizes current knowledge of the mechanisms of resistance to ALK-targeted therapy in lung cancer, including both primary and acquired mechanisms, treatment strategies following resistance, recent therapeutic advances, and the impact of the immune system and tumor microenvironment. A deeper understanding of ALK-targeted therapy resistance is critical for developing new treatment strategies and may provide important insights to guide the diagnosis, treatment, and management of patients with resistant ALK⁺ lung cancer.

Cancers doi: 10.20517/cdr.2025.124

Authors: Chao Fang,Qin Zhang,Rui Fang,Ying Li,Jing Bai,Xiaojing Huang,Jingting Lu,Dongsheng Chen,Yanxiang Zhang,Zuhong Chen

Aim: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; however, their efficacy in head and neck cancer (HNC) remains limited, with only a minority of patients achieving durable responses. Understanding the molecular mechanisms underlying ICI resistance in HNC is therefore crucial.

Methods: We conducted an integrative analysis of genomic, transcriptomic, and clinical data from 139 ICI-treated HNC patients (MSKCC cohort) and 502 treatment-naïve HNC cases (TCGA cohort). ROS1 mutation status, tumor mutational burden (TMB), neoantigen load, immune cell infiltration (via CIBERSORT), and immune-related gene expression were evaluated. Gene set enrichment analysis (GSEA) was performed to identify dysregulated pathways. Survival outcomes were assessed using Kaplan-Meier analysis and Cox regression, with statistical significance defined as P < 0.05.

Results: Patients harboring ROS1 mutations exhibited significantly poorer outcomes following ICI therapy, with shorter median overall survival [OS: 5.0 vs. 11.0 months, hazard ratio (HR) = 3.22, 95%CI: 1.26-8.19, P = 0.011] compared to ROS1 wild-type counterparts. Multivariate analysis confirmed ROS1 mutation as an independent predictor of poor OS in ICI-treated patients (HR = 4.78, 95%CI: 1.70-13.43, P = 0.003). In contrast, ROS1 mutations showed no prognostic significance in the treatment-naïve TCGA-HNC cohort (P = 0.26), confirming their role as a predictive (not prognostic) biomarker for ICI response. Interestingly, despite exhibiting higher TMB and neoantigen levels, ROS1-mutant patients showed inferior survival, underscoring the context-dependent limitations of TMB as a predictive biomarker. Mechanistically, ROS1-mutant tumors displayed an immunosuppressive tumor microenvironment characterized by diminished CD8⁺ T cell infiltration, attenuated interferon-γ signaling, and downregulation of immune-related genes (CXCL9, CXCL10, IFNG, PD-L1). GSEA revealed enrichment of MYC pathway activity in ROS1-mutant tumors, which suppressed antigen presentation and T cell activation pathways.

Conclusion: ROS1 mutations drive ICI resistance in HNC by promoting an immunosuppressive TME via MYC-mediated transcriptional reprogramming, impairing antigen presentation and T cell function. Incorporating ROS1 status into biomarker panels may improve patient stratification and guide combinatorial therapies targeting both immune evasion and oncogenic pathways.

Cancers doi: 10.20517/cdr.2025.90

Authors: Chunwei Li,Ziqiang Liu,Dezheng Kong,Zhengze Li,Lifeng Li

Lactylation, a novel lactate-derived lysine post-translational modification (PTM), has emerged as a critical epigenetic regulator driving drug resistance within the tumor microenvironment (TME). This review systematically delineates the enzymatic underpinnings of lactylation, its induction via the glycolysis-lactate axis influenced by key TME features (hypoxia, inflammation), and its multifaceted roles in promoting resistance. Specifically, lactylation orchestrates transcriptional reprogramming of resistance-associated genes (e.g., oncogenes, immune checkpoints, epithelial–mesenchymal transition factors), enhances DNA damage repair capacity (e.g., via NBS1/MRE11 lactylation), activates pro-survival autophagy, and modulates immunosuppressive signaling pathways (e.g., PI3K/AKT, NF-κB, JAK/STAT). Furthermore, it facilitates critical resistance phenotypes including immune evasion, metastasis, and angiogenesis. The review summarizes emerging therapeutic strategies targeting lactylation, such as inhibition of lactate production (LDHA/LDHB), lactate transport (MCT1/4), lactyltransferases (e.g., p300), or downstream effectors, highlighting their potential to overcome multifactorial resistance. However, elucidating the context-dependent roles, crosstalk with other PTMs, and developing specific inhibitors remain crucial for translating these insights into effective clinical interventions against resistant tumors.

Cancers doi: 10.20517/cdr.2025.28

Authors: Ahmad Dawalibi,Mohamad Bakir,Khalid S. Mohammad

Bone metastases represent frequent and severe complications in various cancers, notably impacting prognosis and quality of life. This review article delves into the genetic and epigenetic mechanisms underpinning drug resistance in bone metastases, a key challenge in effective cancer treatment. The development of drug resistance in cancer can manifest as either intrinsic or acquired, with genetic heterogeneity playing a pivotal role. Intrinsic resistance is often due to pre-existing mutations, while acquired resistance evolves through genetic and epigenetic alterations during treatment. These alterations include mutations in driver genes like TP53 and RB1, epigenetic modifications such as DNA methylation and histone changes, and pathway alterations, notably involving RANK-RANKL signaling and the PI3K/AKT/mTOR cascade. Recent studies underline the significance of the tumor microenvironment in fostering drug resistance, with components such as cancer-associated fibroblasts and hypoxia playing crucial roles. The interactions between metastatic cancer cells and the bone microenvironment facilitate survival and the proliferation of drug-resistant clones. This review highlights the necessity of understanding these complex interactions to develop targeted therapies that can overcome resistance and improve treatment outcomes. Current therapeutic strategies and future directions are discussed, emphasizing the integration of genomic profiling and targeted interventions in managing bone metastases. The evolving landscape of genetic research, including the application of next-generation sequencing and CRISPR technology, offers promising avenues for novel and more effective therapeutic strategies. This comprehensive exploration aims to provide insights into the molecular intricacies of drug resistance in bone metastases, paving the way for improved clinical management and patient care.

Cancers doi: 10.20517/cdr.2025.97

Authors: Jing Wu,Peng-Fei Zhang,Yu Zeng,Ya-Nan Hai,Kun-Ming Zhang,Shu Dong,Ji-Chong Xu,Lan-Lin Zhang,Zhi-Xiong Wu,Hong Jiang

Aim: The immune evasion mechanisms of gastric cancer are complex, involving various cellular dysfunctions within the tumor microenvironment. Recently, there has been growing interest in how cancer-associated fibroblasts (CAFs) contribute to tumor immune evasion. However, the precise molecular pathways through which CAFs drive immune escape in the context of gastric cancer are not yet fully elucidated.

Methods: The abundance of FAP⁺CAFs in gastric cancer tissues was assessed by immunohistochemistry (IHC), and its correlation with tumor sensitivity to PD-1 monoclonal antibody therapy was analyzed. To study the effect of FAP⁺CAFs on naive CD4⁺ T cell differentiation, co-culture experiments were conducted. The underlying molecular mechanisms were further investigated through western blotting and in vivo animal experiments.

Results: FAP⁺CAFs were significantly increased in gastric cancer tissues resistant to PD-1 monoclonal antibody, and a positive correlation was found with Th2 cells. Additionally, the expression and secretion of IL-31 in FAP⁺CAFs cells were elevated. Mechanistically, IL-31 interacts with the IL-31R expressed on naive CD4⁺ T cells, leading to the activation of the STAT6 signaling pathway. This cascade facilitates the differentiation of naive CD4⁺ T cells into Th2 cells, thereby contributing to resistance against anti-PD-1 therapy in gastric cancer.

Conclusion: FAP⁺CAFs may reduce sensitivity to anti-PD-1 therapy in gastric cancer by promoting Th2 polarization of naive CD4⁺ T cells via the IL-31/STAT6 signaling pathway. Targeting this axis could offer a potential strategy to improve immunotherapy outcomes, although further validation is required.

Cancers doi: 10.20517/cdr.2025.105

Authors: Xinqi Teng,Yiming Wang,Qiang Qu,Weixin Xu,Haihui Zhuang,Yiwen Wei,Yinghuan Dai,Jian Qu

Aim: Glioblastoma (GBM) is the most malignant grade of glioma, characterized by high recurrence, poor prognosis, and frequent chemoresistance. There is an urgent need for alternative treatment strategies. In this study, we evaluated the effects of THZ2, a covalent inhibitor targeting the super-enhancer (SE) component CDK7, on GBM growth and chemoresistance. We also used another SE inhibitor, JQ1, to further validate the inhibitory effects of targeting SEs in GBM, thereby providing new treatment strategies for patients.

Methods: A variety of in vitro and in vivo assays were performed to explore the anti-GBM effects of SE inhibitors. We assessed the effects of SE inhibitors in combination with temozolomide (TMZ) on GBM cells and calculated the combination index. Additionally, CUT&RUN assays were conducted to examine protein-DNA interactions.

Results: THZ2 inhibited the proliferation, migration, and invasion of GBM cells and induced cell cycle arrest and apoptosis. Furthermore, both THZ2 and JQ1 exhibited synergistic antitumor effects when combined with TMZ in GBM cells. Notably, THZ2 reversed TMZ resistance in GBM cells by suppressing the expression of the SE-associated gene SOX9. We also found that SOX9, CDK7, and BRD4 interact with histone H3K27ac.

Conclusion: Our findings demonstrate that SE inhibitors exert antitumor effects in GBM and act synergistically with TMZ. THZ2 may enhance chemosensitivity by downregulating the SE-related gene SOX9, and it holds promise as a novel therapeutic agent for GBM patients.

Cancers doi: 10.20517/cdr.2025.69

Authors: Suryendu Saha,Samikshya Mahapatra,Sinjan Khanra,Barnalee Mishra,Biswajit Swain,Diksha Malhotra,Swarnali Saha,Venketesh K. Panda,Kavita Kumari,Sarmistha Jena,Sandeep Thakur,Pawan K. Singh,Gopal C. Kundu

Breast cancer continues to be the primary cause of cancer-related deaths among women globally, with increased rates of incidence and mortality, highlighting the critical need for effective treatment strategies. Recent developments have introduced a variety of treatment options that address the molecular diversity of breast cancer; nonetheless, drug resistance remains a significant barrier to achieving favorable results. This review explains the crucial role of genetic and epigenetic changes in contributing to therapeutic resistance, in addition to other factors such as increased drug efflux, enhanced DNA repair, evasion of senescence, tumor heterogeneity, the tumor microenvironment (TME), and epithelial-to-mesenchymal transition (EMT). Genetic modifications, including mutations in oncogenes and tumor suppressor genes, disrupt essential signaling pathways, facilitating resistance to chemotherapy and targeted therapies. At the same time, epigenetic modifications - like DNA methylation, alterations to histones, and dysregulation of non-coding RNAs - reprogram gene expression, supporting adaptive resistance mechanisms. These molecular abnormalities contribute to the plasticity of tumors, allowing cancer cells to evade therapeutic approaches. This review consolidates recent discoveries regarding how these genetic and epigenetic modifications affect treatment responses and resistance in breast cancer, highlighting their interaction with disease advancement. By pinpointing new drug targets, including immunotherapeutic strategies, this article seeks to shed light on the molecular underpinnings of chemoresistance, aiding in the refinement of existing treatment protocols. A more profound understanding of these mechanisms offers the potential for developing precision therapies to overcome resistance, reduce relapse rates, and improve clinical outcomes for breast cancer patients.

Cancers doi: 10.20517/cdr.2025.34

Authors: Chengming Yang,Lushan Yang,Yuchen Feng,Xingyi Song,Shu Bai,Sheng Zhang,Mingjuan Sun

Tumor organoids were modeled in vitro to mimic in vivo culture conditions, allowing tumor-derived tissue cells or isolated and purified tumor stem cells to self-assemble into 3D preclinical models that are similar to tissues and organs in vivo. Compared with traditional models, tumor organoids not only resemble parental tumors in histology and genomics, capturing their heterogeneity and drug response, but also provide an efficient platform for long-term culture, maintaining genetic stability and enabling gene manipulation. Therefore, tumor organoids have unique advantages in cancer drug resistance research. The paper covers: (1) Modeling methods of epithelial and non-epithelial tumor organoids, with special emphasis on the modeling of drug-resistant organoids; (2) Their use in drug resistance research, split into i. Therapeutic exploration (drug testing and screening) and ii. Mechanism investigation (use drug-resistant organoids to study drug resistance), including methods and findings from various teams.

Cancers doi: 10.20517/cdr.2025.47

Authors: Chao Li,Longxiang Wu,Bowen Zhong,Yu Gan,Lei Zhou,Shuo Tan,Weibin Hou,Kun Yao,Bingzhi Wang,Zhenyu Ou,Shengwang Zhang,Wei Xiong

Introduction: Prostate cancer (PCa) continues to be a significant cause of mortality among men, with treatment resistance often influenced by the complexity of the tumor microenvironment (TME). This study aims to develop an immune-centric prognostic model that correlates TME dynamics, genomic instability, and the heterogeneity of drug resistance in PCa.

Methods: Multi-omics data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were integrated, encompassing transcriptomic profiles of 554 TCGA-PRAD samples and 329 external validation samples. Immune cell infiltration was assessed using CIBERSORT and ESTIMATE. Weighted gene co-expression network analysis (WGCNA) was employed to identify immune-related modules. Single-cell RNA sequencing (ScRNA-seq) of 835 PCa cells uncovered subtype-specific resistance patterns. Prognostic models were constructed using least absolute shrinkage and selection operator (LASSO) regression and subsequently validated experimentally in PCa cell lines.

Results: Two immune subtypes were identified: high-risk subgroups displayed TP53 mutations, increased tumor mutation burden (TMB), and enriched energy metabolism pathways. ScRNA-seq delineated three PCa cell clusters, with high-risk subtypes being sensitive to bendamustine/dacomitinib and resistant to apalutamide/neratinib. A 10-gene prognostic model (e.g., MUC5B, TREM1) categorized patients into high/low-risk groups with distinct survival outcomes (log-rank P < 0.0001). Validation in external datasets confirmed the robust predictive accuracy (AUC: 0.854-0.889). Experimental assays verified subtype-specific drug responses and dysregulation of key model genes.

Discussion: This study establishes a TME-driven prognostic framework that connects immune heterogeneity, genomic instability, and therapeutic resistance in PCa. By pinpointing metabolic dependencies and subtype-specific vulnerabilities, our findings provide actionable strategies to circumvent treatment failure, such as targeting energy metabolism or tailoring therapies based on resistance signatures.

Cancers doi: 10.20517/cdr.2025.73

Authors: Dongye Huang,Qianwen Liu,Chang Liu,Jingna Cao,Senmin Zhang,Huijiao Cao,Wenkuan Chen

Thyroid cancer, particularly papillary thyroid cancer (PTC), represents the most prevalent endocrine malignancy. Despite advancements in therapeutic strategies, drug resistance significantly hampers clinical outcomes. Autophagy, an evolutionarily conserved cellular degradation pathway, acts paradoxically in thyroid cancer by promoting either tumor cell survival or cell death, thus influencing therapeutic resistance. Increasing evidence highlights microRNAs (miRNAs), small non-coding RNAs, as critical regulators of autophagy through precise modulation of autophagy-related genes (ATGs) and signaling pathways. miRNA-mediated autophagy can either enhance chemotherapeutic efficacy or facilitate resistance, depending on the cellular context and miRNA targets. This review summarizes recent insights into miRNA-autophagy interactions underlying drug resistance in thyroid cancer, emphasizing key miRNAs, including miR-125b, miR-144, miR-30d, and miR-9-5p. Understanding the complex regulatory networks connecting miRNAs and autophagy provides promising avenues for developing novel therapeutic strategies to overcome resistance in refractory thyroid cancer.

Cancers doi: 10.20517/cdr.2025.26

Authors: Ping Xing,Chenghui Yang,Hanwen Hu,Tianyi Qian,Bojian Xie,Jian Huang,Zhen Wang

Antibody-drug conjugates (ADCs), inspired by Paul Ehrlich’s “magic bullet” concept to target cancer cells with cytotoxic drugs while sparing healthy cells, represent a transformative approach in breast cancer therapy. From early agents (e.g., gemtuzumab ozogamicin) to second-generation trastuzumab emtansine (T-DM1) and third-generation trastuzumab deruxtecan (T-DXd)/disitamab vedotin (RC48), ADCs have demonstrated significant clinical benefits, including improved progression-free survival (PFS) and overall survival (OS) in breast cancer, with several approved for clinical use. Ongoing preclinical and clinical studies are rigorously exploring ADC combinations with molecular targeted agents, chemotherapy, and immunotherapy. However, de novo and acquired resistance remains a critical barrier to maximizing therapeutic efficacy. This review summarizes ADC mechanisms and clinical outcomes in breast cancer, explores resistance mechanisms, and dissects the biological rationale for combination strategies, aiming to identify novel payloads that enhance patient outcomes.

Cancers doi: 10.20517/cdr.2025.35

Authors: Juncheng Su,Jiahui Wang,Weilin Chen,Yingjie Xu,Wen Yang,Weiwei Liu,Zheng Wang,Masha Huang

Aim: Bevacizumab has long been a cornerstone in the treatment of colorectal cancer (CRC), serving as a fundamental antiangiogenic therapeutic option. However, a significant proportion of patients exhibit insensitivity to bevacizumab, and no reliable biomarker has been established to predict treatment efficacy. Notably, while many angiogenic factors in tumors have been extensively studied, they have failed to consistently demonstrate reliable predictive value for patient survival outcomes in CRC. This study is designed to screen tumor biomarkers with predictive value for bevacizumab resistance in CRC.

Methods: Online CRC databases with bevacizumab treatment were downloaded from the GEO datasets along with the TCGA database, which were then analyzed to generate genes overexpressed in bevacizumab non-responders. In vitro experiments using colorectal cancer cell lines were then performed to explore the underlying mechanism of the candidate gene that impacts bevacizumab efficacy. Finally, clinical samples of CRC were collected to validate the predictive effect of the candidate gene on bevacizumab efficacy.

Results: We conducted comprehensive analyses of CRC patient datasets, identifying MAGEA3 as a pivotal gene that is not only highly upregulated in bevacizumab-resistant primary CRC but also strongly associated with poor overall survival prognosis. Our in vitro experiments revealed a novel mechanistic insight: MAGEA3 specifically inhibits the expression and secretion of VEGF through the mTOR signaling pathway in colorectal cancer cells, while exhibiting minimal impact on other key angiogenic factors such as PDGF, FGF, and ANGPT2. This selective regulation of VEGF provides a molecular basis for MAGEA3's role in bevacizumab resistance. Furthermore, we discovered that MAGEA3 significantly impairs mitochondrial function in cancer cells, suggesting an additional layer of complexity in its oncogenic role. Clinically, our findings demonstrated that high baseline levels of MAGEA3 in CRC patients were strongly associated with worse progression-free survival (PFS) following bevacizumab treatment.

Conclusion: Collectively, these findings position MAGEA3 as a promising predictive biomarker for bevacizumab resistance in CRC, offering a potential solution to the longstanding challenge of treatment stratification.

Cancers doi: 10.20517/cdr.2025.41

Authors: Leyi Yao,Baoyi Jiang,Dacai Xu

Cancer cells often develop tolerance to chemotherapy, targeted therapy, and immunotherapy drugs either before or during treatment. The significant heterogeneity among various tumors poses a critical challenge in modern cancer research, particularly in overcoming drug resistance. Copper, as an essential trace element in the body, participates in various biological processes of diseases, including cancers. The growth of many types of tumor cells exhibits a heightened dependence on copper. Thus, targeting copper metabolism or inducing cuproptosis may be potential ways to overcome cancer drug resistance. Copper chelators have shown potential in overcoming cancer drug resistance by targeting copper-dependent processes in cancer cells. In contrast, copper ionophores, copper-based nanomaterials, and other small molecules have been used to induce copper-dependent cell death (cuproptosis) in cancer cells, including drug-resistant tumor cells. This review summarizes the regulation of copper metabolism and cuproptosis in cancer cells and the role of copper metabolism and cuproptosis in cancer drug resistance, providing ideas for overcoming cancer resistance in the future.

Cancers doi: 10.20517/cdr.2025.157

Authors: Zirui Dong,Shoukang Li,Mingfeng Li,Meiyin Fan,Kailei Chen,Anshu Li,Keshan Wang,Xiaoping Zhang

Renal cell carcinoma (RCC), the predominant form of kidney cancer, accounts for 90% of cases and poses significant clinical challenges due to frequent late-stage or metastatic presentation. Based on literature and surveillance data from 2020 to 2025, despite therapeutic advancements, metastatic RCC still exhibits a dismal 5-year survival rate. While tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor/platelet-derived growth factor pathways have been a cornerstone of RCC treatment, their efficacy is limited by acquired resistance, necessitating novel strategies to improve patient outcomes. This review synthesizes advancements from 2020 to 2025 in understanding and overcoming TKI resistance in RCC. We explored emerging mechanisms of resistance, including tumor microenvironment remodeling, metabolic reprogramming, and activation of alternative survival pathways. Furthermore, we evaluated innovative therapeutic approaches. By consolidating recent insights, this review highlights promising strategies to circumvent resistance and underscores the importance of personalized, mechanism-driven therapies. Our analysis aims to inform future research directions and clinical translation, ultimately advancing the management of TKI-resistant RCC.

Cancers doi: 10.20517/cdr.2025.49

Authors: Meijiang Zhou,Zhiwen Huang,Zijun Ma,Jun Chen,Shunping Lin,Xuwei Yang,Quan Gong,Zachary Braunstein,Yingying Wei,Xiaoquan Rao,Jixin Zhong

Antibody-Drug Conjugates (ADCs) have achieved significant success in cancer therapy by combining the targeting specificity of monoclonal antibodies with cytotoxic payloads. However, the concomitant issue of drug resistance has become increasingly prominent, with primary mechanisms including alterations in target antigen expression, impaired drug transport, and inhibition of cell death pathways. ADCs have also shown emerging therapeutic potential in the treatment of autoimmune diseases; for instance, ABBV-3373 has achieved initial success in this area, yet it also faces unique challenges such as the safety of long-term administration, immunogenicity, and heterogeneity of target cells. Addressing these challenges requires multidimensional innovations, including optimizing molecular design, exploring combination therapy strategies, and introducing artificial intelligence (AI)-assisted development. These efforts aim to transition ADCs from the traditional “targeted killing” paradigm to intelligent and personalized precision delivery systems, thereby offering more therapeutic options for patients with cancer and autoimmune diseases.

Cancers doi: 10.20517/cdr.2025.18

Authors: Ronghao Qin,Yuxing Liang,Fuling Zhou

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are genetically heterogeneous malignancies of hematopoietic stem cells, characterized by complex mutations and a high risk of drug resistance and relapse. Patient-derived xenograft (PDX) models are dynamic entities transplanted with leukemia stem cells (LSCs), retaining patients’ biological and genetic characteristics. By elucidating LSCs, clonal dynamics, and microenvironment interaction, PDXs facilitate the preclinical evaluation of therapy sensitivity, including immunotherapies, epigenetic therapies, and other agents targeting mutated proteins or apoptosis. The application of PDXs has provided translational evidence for various studies with reliable clinical relevance. Additionally, conventional PDXs remain a robust tool in identifying drug resistance compared with other models, and their potential is further unleashed when examined in large cohorts or combined with novel technologies, which not only enhances our understanding of acute leukemia biology but also enables the discovery and identification of novel biomarkers. In this review, we present the application of PDX models for acute leukemia resistance, including mechanism investigation, therapy evaluation, and associated challenges.