<area date-time="y9VVQ5hk"></area> Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. VSports app下载.

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely V体育官网. .

. 2019 Mar 20;10(1):1295.
doi: 10.1038/s41467-019-09312-9.

"V体育ios版" Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer

Elizabeth L Christie  1   2 , Swetansu Pattnaik  3 , Jessica Beach  1 , Anthony Copeland  1 , Nineveh Rashoo  1 , Sian Fereday  1 , Joy Hendley  1 , Kathryn Alsop  1 , Samuel L Brady  4 , Greg Lamb  4 , Ahwan Pandey  1 , Anna deFazio  5   6   7 , Heather Thorne  1 , Andrea Bild  4   8 , David D L Bowtell  9   10   11
Affiliations

Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer

Elizabeth L Christie et al. Nat Commun. .

Abstract

ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs VSports手机版. Here we report that ovarian and breast samples from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1. Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi. .

PubMed Disclaimer

Conflict of interest statement

D. B. receives research grant funding from Genentech, Roche & Astra Zeneca, and is establishing a research collaboration with BeiGene. BeiGene has developed pamiparb which is a non-P-gp substrate PARPi V体育安卓版. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
ABCB1 in recurrent HGSC and breast cancer patients. a Patients ranked by ABCB1 expression level in recurrent HGSC samples (n = 108), presence of ABCB1 transcriptional fusions was observed in 20 patients, the bar colour indicates the fusions present. Gene structure of 10 of the 13 fusion partner genes is shown. b Schematic representation of the structure of a majority of the transcriptional fusions identified in which non-coding exons of partner genes (red) were fused to exon 2 onwards of ABCB1 (green). c Clustering of breakpoints at the 3′ end of intron 1 of ABCB1, green triangles indicate SLC25A40–ABCB1 fusion breakpoints, red are other fusion partners. d Schematic representation of the structure of the SV involving ABCB1 in Patient 9. e Breast cancer patients ranked by ABCB1 expression in recurrent or end-stage samples (n = 30 patients, 45 samples). ABCB1 fusions were observed in nine patients (blue or green dots)
Fig. 2
Fig. 2
Characteristics of fusion partners. a Mean expression of all genes from normal fallopian tube, primary HGSC and primary breast cancer RNAseq data. Gene expression was rank ordered. Fusion partners are highlighted in red, ABCB1 in green. b Chromosomal location of fusion partners, with a majority located on chromosome 7 (boxed). c Number of SVs, by type, in recurrent HGSC samples described as ABCB1 fusion-positive or negative
Fig. 3
Fig. 3
Association between treatment and fusion status. a Associations were identified between the total number of chemotherapy lines and number of MDR1 substrate chemotherapy lines and fusion positivity. b The number of lines of paclitaxel were significantly associated with fusion positivity, the number of lines of liposomal doxorubicin was not significant (Wilcoxon test). c–e CA125 serum marker profile for Patients 10, 15 and 7 where multiple recurrent ascites samples were tested for ABCB1 expression (by Q-RT-PCR) and fusions, as indicated in graph inset
Fig. 4
Fig. 4
Resensitisation of a fusion-positive cell line with an MDR1 inhibitor. a Fusion-specific RT-PCR demonstrates that patient-derived cell line AOCS18.5 is positive for the SLC25A40–ABCB1 fusion (F). C corresponds to RT-PCR using primers to measure ABCB1 expression. Ladder is shown in base pairs. b Western blot shows MDR1 expression in fusion-positive line AOCS18.5 but not in fusion-negative line AOCS21.2. c MDR1 expression in AOCS18.5 by immunofluorescence. Inset shows antibody isotype control. d IC50 plots in AOCS18.5 and non-fusion AOCS21.2 cell lines, showing a fusion-specific increase in paclitaxel sensitivity, but sensitivity to non-substrate cisplatin, in the presence of the MDR1 inhibitor elacridar (n = 3 replicates). Error bars indicate ± SEM. For some points, error bars are shorter than the height of the symbol and are not shown
See this image and copyright information in PMC

References

    1. Patch AM, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015;521:489–494. doi: 10.1038/nature14410. - "V体育官网" DOI - PubMed
    1. Brady SW, et al. Combating subclonal evolution of resistant cancer phenotypes. Nat. Commun. 2017;8:1231. doi: 10.1038/s41467-017-01174-3. - "V体育官网入口" DOI - PMC - PubMed
    1. Robey RW, et al. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat. Rev. Cancer. 2018;18:452–464. doi: 10.1038/s41568-018-0005-8. - DOI - PMC - PubMed
    1. Zheng Z, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat. Med. 2014;20:1479–1484. doi: 10.1038/nm.3729. - DOI - PubMed
    1. Ween MP, Armstrong MA, Oehler MK, Ricciardelli C. The role of ABC transporters in ovarian cancer progression and chemoresistance. Crit. Rev. Oncol. Hematol. 2015;96:220–256. doi: 10.1016/j.critrevonc.2015.05.012. - DOI - PubMed

Publication types

"VSports在线直播" MeSH terms

Substances