Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas
Abstract
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.
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BibTeX
@article{meghani2026multifaceted,
title = {{Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas}},
author = {Khyati Meghani and Walker Fuchs and Alexandre Detappe and Pascal Drané and Ewa Gogola and Sven Rottenberg and Jos Jonkers and Ursula Matulonis and Elizabeth Swisher and Panagiotis Konstantinopoulos and Dipanjan Chowdhury},
journal = {Cell Reports},
year = {2026},
month = oct,
doi = {10.1016/j.celrep.2018.03.038},
url = {https://hal.science/hal-05829505v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas
AU - Khyati Meghani
AU - Walker Fuchs
AU - Alexandre Detappe
AU - Pascal Drané
AU - Ewa Gogola
AU - Sven Rottenberg
AU - Jos Jonkers
AU - Ursula Matulonis
AU - Elizabeth Swisher
AU - Panagiotis Konstantinopoulos
AU - Dipanjan Chowdhury
PY - 2026
DA - 2026/10/21
JO - Cell Reports
DO - 10.1016/j.celrep.2018.03.038
UR - https://hal.science/hal-05829505v1
AB - 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.
SN - 2211-1247
SN - 2211-1247
ER -