Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer

被引：131

作者：

Choi, Young Eun ^{[1
]}

Meghani, Khyati ^{[1
]}

Brault, Marie-Eve ^{[1
]}

Leclerc, Lucas ^{[1
]}

He, Yizhou J. ^{[1
]}

Day, Tovah A. ^{[2
]}

Elias, Kevin M. ^{[3
]}

Drapkin, Ronny ^{[4
]}

Weinstock, David M. ^{[2
]}

Dao, Fanny ^{[5
]}

Shih, Karin K. ^{[5
]}

Matulonis, Ursula ^{[2
]}

Levine, Douglas A. ^{[5
]}

Konstantinopoulos, Panagiotis A. ^{[2
]}

Chowdhury, Dipanjan ^{[1
]}

机构：

[1] Harvard Univ, Dana Farber Canc Inst, Div Genom Stabil & DNA Repair, Dept Radiat Oncol,Sch Med, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA

[3] Brigham & Womens Hosp, Dept Obstet & Gynecol & Reprod Biol, Div Gynecol Oncol, Boston, MA 02215 USA

[4] Univ Penn, Perelman Sch Med, Dept Obstet & Gynecol, Ovarian Canc Res Ctr, Philadelphia, PA 19104 USA

[5] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA

来源：

CELL REPORTS | 2016年 / 14卷 / 03期

关键词：

DNA-DAMAGE; HOMOLOGOUS RECOMBINATION; REPAIR; DEFICIENCY; 53BP1; KU;

D O I：

10.1016/j.celrep.2015.12.046

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

High-grade serous ovarian carcinomas (HGSOCs) with BRCA1/2 mutations exhibit improved outcome and sensitivity to double-strand DNA break (DSB)inducing agents (i.e., platinum and poly(ADP-ribose) polymerase inhibitors [PARPis]) due to an underlying defect in homologous recombination (HR). However, resistance to platinum and PARPis represents a significant barrier to the long-term survival of these patients. Although BRCA1/2-reversion mutations are a clinically validated resistance mechanism, they account for less than half of platinum-resistant BRCA1/2-mutated HGSOCs. We uncover a resistance mechanism by which a microRNA, miR-622, induces resistance to PARPis and platinum in BRCA1 mutant HGSOCs by targeting the Ku complex and restoring HR-mediated DSB repair. Physiologically, miR-622 inversely correlates with Ku expression during the cell cycle, suppressing non-homologous end-joining and facilitating HR-mediated DSB repair in S phase. Importantly, high expression of miR-622 in BRCA1-deficient HGSOCs is associated with worse outcome after platinum chemotherapy, indicating microRNA-mediated resistance through HR rescue.

引用

页码：429 / 439

页数：11

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