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

被引：154

作者：

Christie, Elizabeth L. ^{[1
,2
]}

Pattnaik, Swetansu ^{[3
]}

Beach, Jessica ^{[1
]}

Copeland, Anthony ^{[1
]}

Rashoo, Nineveh ^{[1
]}

Fereday, Sian ^{[1
]}

Hendley, Joy ^{[1
]}

Alsop, Kathryn ^{[1
]}

Brady, Samuel L. ^{[4
]}

Lamb, Greg ^{[4
]}

Pandey, Ahwan ^{[1
]}

deFazio, Anna ^{[5
,6
,7
]}

Thorne, Heather ^{[1
]}

Bild, Andrea ^{[4
,8
]}

Bowtell, David D. L. ^{[1
,2
,3
]}

机构：

[1] Peter MacCallum Canc Ctr, Melbourne, Vic 3000, Australia

[2] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia

[3] Garvan Inst Med Res, Kinghorn Canc Ctr, Darlinghurst, NSW 2010, Australia

[4] Univ Utah, Salt Lake City, UT 84112 USA

[5] Westmead Inst Med Res, Ctr Canc Res, Westmead, NSW 2145, Australia

[6] Westmead Hosp, Dept Gynaecol Oncol, Westmead, NSW 2145, Australia

[7] Univ Sydney, Sydney, NSW 2052, Australia

[8] City Hope Natl Med Ctr, Los Angeles, CA 91010 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

CHEMOTHERAPY RESISTANCE; ALIGNER;

D O I：

10.1038/s41467-019-09312-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. 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.

引用

页数：10

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