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

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, r...

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Published in:Cell reports (Cambridge) Vol. 14; no. 3; pp. 429 - 439
Main Authors: Choi, Young Eun, Meghani, Khyati, Brault, Marie-Eve, Leclerc, Lucas, He, Yizhou J., Day, Tovah A., Elias, Kevin M., Drapkin, Ronny, Weinstock, David M., Dao, Fanny, Shih, Karin K., Matulonis, Ursula, Levine, Douglas A., Konstantinopoulos, Panagiotis A., Chowdhury, Dipanjan
Format: Journal Article
Language:English
Published: United States Elsevier Inc 26.01.2016
Elsevier
Subjects:
Animals
Antigens, Nuclear - genetics
Antigens, Nuclear - metabolism
Antineoplastic Agents - pharmacology
Base Sequence
BRCA1 Protein - genetics
BRCA1 Protein - metabolism
Cell Line, Tumor
Disease-Free Survival
DNA End-Joining Repair - drug effects
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Female
Homologous Recombination - drug effects
Humans
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Ku Autoantigen
Mice
MicroRNAs - antagonists & inhibitors
MicroRNAs - genetics
MicroRNAs - metabolism
Oligonucleotides, Antisense - metabolism
Organoplatinum Compounds - pharmacology
Ovarian Neoplasms - genetics
Ovarian Neoplasms - mortality
Ovarian Neoplasms - pathology
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
RNA Interference
Sequence Alignment
Tumor Suppressor p53-Binding Protein 1
ISSN:2211-1247, 2211-1247
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Summary: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. [Display omitted] •miR-622 induces resistance to PARP inhibitors and cisplatin in BRCA1-deficient cells•miR-622 levels in BRCA1-mutant ovarian tumors correlates with survival of patients•The Ku complex is directly downregulated by miR-622 to suppress the NHEJ pathway•MiR-622 helps to balance HR and NHEJ pathways for DSB repair during the cell cycle Choi et al. show that expression of miR-622 induces resistance to PARP inhibitors and cisplatin in BRCA1-mutant ovarian tumors and correlates with survival of patients. miR-622 suppresses NHEJ by downregulating expression of the Ku complex and facilitates homologous recombination mediated repair of DNA double-strand breaks (DSBs) in the S phase of cycling cells.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2015.12.046