Platinum and PARP inhibitor resistance due to verexpression of microRNA-622 in BRCA1-mutant ovarian cancer Journal Article
| Authors: | Choi, Y. E.; Meghani, K.; Brault, M. E.; Leclerc, L.; He, Y. Z. J.; Day, T. A.; Elias, K. M.; Drapkin, R.; Weinstock, D. M.; Dao, F.; Shih, K. K.; Matulonis, U.; Levine, D. A.; Konstantinopoulos, P. A.; Chowdhury, D. |
| Article Title: | Platinum and PARP inhibitor resistance due to verexpression of microRNA-622 in BRCA1-mutant ovarian cancer |
| Abstract: | 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. |
| Keywords: | homologous recombination; resection; repair; dna-damage; cell-cycle; deficiency; breaks; ku; 53bp1 |
| Journal Title: | Cell Reports |
| Volume: | 14 |
| Issue: | 3 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2016-01-26 |
| Start Page: | 429 |
| End Page: | 439 |
| Language: | English |
| ACCESSION: | WOS:000368701600004 |
| DOI: | 10.1016/j.celrep.2015.12.046 |
| PROVIDER: | wos |
| PMCID: | PMC4731274 |
| PUBMED: | 26774475 |
| Notes: | Article -- Source: Wos |
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