title: Platinum and PARP Inhibitor Resistance Due to Overexpression 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.
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Choi
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Khyati
authors.initials: K
authors.lastname: Meghani
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Brault
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Leclerc
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yizhou J
authors.initials: YJ
authors.lastname: He
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Tovah A
authors.initials: TA
authors.lastname: Day
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Elias
authors.affiliation: Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Fanny
authors.initials: F
authors.lastname: Dao
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Karin K
authors.initials: KK
authors.lastname: Shih
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ursula
authors.initials: U
authors.lastname: Matulonis
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: panagiotis_konstantinopoulos@dfci.harvard.edu.
authors.forename: Panagiotis A
authors.initials: PA
authors.lastname: Konstantinopoulos
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: dipanjan_chowdhury@dfci.harvard.edu.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D059766:DNA End-Joining Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072200:Ku Autoantigen; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D016415:Sequence Alignment; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D009944:Organoplatinum Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen