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Review
. 2018 Jul 24:8:267.
doi: 10.3389/fonc.2018.00267. eCollection 2018.

Drug Resistance in Non-Small Cell Lung Cancer: A Potential for NOTCH Targeting?

Venus Sosa Iglesias  1 , Lorena Giuranno  1 , Ludwig J Dubois  1 , Jan Theys  1 , Marc Vooijs  1
Affiliations
Review

"VSports" Drug Resistance in Non-Small Cell Lung Cancer: A Potential for NOTCH Targeting?

Venus Sosa Iglesias et al. Front Oncol. .

Abstract

Drug resistance is a major cause for therapeutic failure in non-small cell lung cancer (NSCLC) leading to tumor recurrence and disease progression. Cell intrinsic mechanisms of resistance include changes in the expression of drug transporters, activation of pro-survival, and anti-apoptotic pathways, as well as non-intrinsic influences of the tumor microenvironment VSports手机版. It has become evident that tumors are composed of a heterogeneous population of cells with different genetic, epigenetic, and phenotypic characteristics that result in diverse responses to therapy, and underlies the emergence of resistant clones. This tumor heterogeneity is driven by subpopulations of tumor cells termed cancer stem cells (CSCs) that have tumor-initiating capabilities, are highly self-renewing, and retain the ability for multi-lineage differentiation. CSCs have been identified in NSCLC and have been associated with chemo- and radiotherapy resistance. Stem cell pathways are frequently deregulated in cancer and are implicated in recurrence after treatment. Here, we focus on the NOTCH signaling pathway, which has a role in stem cell maintenance in non-squamous non-small lung cancer, and we critically assess the potential for targeting the NOTCH pathway to overcome resistance to chemotherapeutic and targeted agents using both preclinical and clinical evidence. .

Keywords: NOTCH/gamma-secretase inhibitor; chemotherapy; non-small cell lung cancer; targeted therapy; treatment resistance. V体育安卓版.

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Figures

Figure 1
Figure 1
Notch and the Hallmarks of Cancer in tumor resistance to chemotherapy and targeted agents in NSCLC. NOTCH1 sustains proliferative signaling by upregulating PI3K/AKT pathway via PTEN repression and induction of IGF-1R under hypoxia. PI3K/AKT and MAPK/ERK/RAS then upregulate HIF-1α in an oxygen-dependent manner. HIF-1α binds to N1 ICD to regulate each other: HIF-1α increases gamma-secretase activity to activate NOTCH signaling whereas factor inhibitor HIF (FIH) hydroxylates and downregulates NICD activity. NOTCH1 upregulates IGF-1R which forms a heterodimer (∞) with EGFR and increases survivin (apoptosis inhibitor) to resist cell death. Cancer cells also resist cell death by upregulating the autophagosomal marker LC3 and/or drug transporters (ABCB1 and ABCG2) mediated by NOTCH-dependent AP1/microRNA-451 or through a glycolysis-associated mechanism via FOXO3a/AKT signaling thus promoting deregulation of cellular energetics. CSL binds to TP53 and they can both repress each other thus evading growth suppressors. NOTCH signaling also has a role in the maintenance of cancer stem cells (CSCs). Chemotherapy induces an enrichment of resistant tumor cells expressing CSC markers (CD133, ALDH, CD44). CSCs have downregulated the AQP2 and CTR1 drug transporters which prevent drug accumulation and reduce dsDNA damage. In addition, CSCs have increased DDR and repair pathways. NOTCH facilitates metastasis by increasing the epithelial–mesenchymal transition (EMT) via an increase in TWIST, SNAIL, SLUG, and ZEB. NOTCH activation can also stimulate endothelial-to-mesenchymal transition (EndMT) which increases the production of cancer-associated fibroblasts (CAF) which are known to be involved in chemotherapy resistance. DLL4 ligand is positively regulated by proangiogenic factors (e.g., VEGF-A, bFGF), IL-6 mediated by STAT3 activation, FOXC protein, N4 ICD, and HIF-1α to induce angiogenesis. DLL4 downregulates VEGFR2 to inhibit VEGF-A and endothelial cell proliferation and migration. DLL4 ligand targeting inhibits tumor progression of human lung adenocarcinomas. Upregulated NOTCH signaling activity has been found in cancers with other genetic alterations/mutations [KRAS, EGFR, HER2, MET, anaplastic lymphoma kinase (ALK), PI3K] with which it cross-talks. Abbreviations: I, inhibitor; DDR, DNA-damage response; miR, microRNA; GSI: gamma-secretase inhibitor; dsDNA, double stranded deoxyribonucleic acid; N4 ICD, NOTCH 4 intracellular domain.
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