Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer
Young Eun Choi,
Khyati Meghani,
Marie-Eve Brault,
Lucas Leclerc,
Yizhou J. He,
Tovah A. Day,
Kevin M. Elias,
Ronny Drapkin,
David M. Weinstock,
Fanny Dao,
Karin K. Shih,
Ursula Matulonis,
Douglas A. Levine,
Panagiotis A. Konstantinopoulos,
Dipanjan Chowdhury
Affiliations
Young Eun Choi
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Khyati Meghani
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Marie-Eve Brault
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Lucas Leclerc
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Yizhou J. He
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Tovah A. Day
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Kevin M. Elias
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Boston, MA 02215, USA
Ronny Drapkin
Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
David M. Weinstock
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Fanny Dao
Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA
Karin K. Shih
Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA
Ursula Matulonis
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Douglas A. Levine
Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA
Panagiotis A. Konstantinopoulos
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Dipanjan Chowdhury
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
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.
