Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas
Khyati Meghani,
Walker Fuchs,
Alexandre Detappe,
Pascal Drané,
Ewa Gogola,
Sven Rottenberg,
Jos Jonkers,
Ursula Matulonis,
Elizabeth M. Swisher,
Panagiotis A. Konstantinopoulos,
Dipanjan Chowdhury
Affiliations
Khyati Meghani
Department of Radiation Oncology, Division of Radiation and Genome Stability, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Walker Fuchs
Department of Radiation Oncology, Division of Radiation and Genome Stability, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Alexandre Detappe
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Pascal Drané
Department of Radiation Oncology, Division of Radiation and Genome Stability, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Ewa Gogola
Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
Sven Rottenberg
Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Laenggassstr. 122, 3012 Bern, Switzerland
Jos Jonkers
Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
Ursula Matulonis
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Elizabeth M. Swisher
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
Panagiotis A. Konstantinopoulos
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Corresponding author
Dipanjan Chowdhury
Department of Radiation Oncology, Division of Radiation and Genome Stability, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Corresponding author
Summary: BRCA1/2-mutated ovarian cancers (OCs) are defective in homologous recombination repair (HRR) of double-strand breaks (DSBs) and thereby sensitive to platinum and PARP inhibitors (PARPis). Multiple PARPis have recently received US Food and Drug Administration (FDA) approval for treatment of OCs, and resistance to PARPis is a major clinical problem. Utilizing primary and recurrent BRCA1/2-mutated carcinomas from OC patients, patient-derived lines, and an in vivo BRCA2-mutated mouse model, we identified a microRNA, miR-493-5p, that induced platinum/PARPi resistance exclusively in BRCA2-mutated carcinomas. However, in contrast to the most prevalent resistance mechanisms in BRCA mutant carcinomas, miR-493-5p did not restore HRR. Expression of miR-493-5p in BRCA2-mutated/depleted cells reduced levels of nucleases and other factors involved in maintaining genomic stability. This resulted in relatively stable replication forks, diminished single-strand annealing of DSBs, and increased R-loop formation. We conclude that impact of miR-493-5p on multiple pathways pertinent to genome stability cumulatively causes PARPi/platinum resistance in BRCA2 mutant carcinomas. : Meghani et al. find that increased expression of miR-493-5p induces resistance to platinum and PARP inhibitors in patient cells harboring BRCA2 mutations by targeting repair pathways involved in maintaining genome stability. Keywords: microRNAs, ovarian cancer, replication fork, BRCA2 mutations, chemotherapeutic resistance, RNA-DNA hybrids, single strand annealing, DSB repair
