Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas.

Meghani, Khyati; Fuchs, Walker; Detappe, Alexandre; Drané, Pascal; Gogola, Ewa; Rottenberg, Sven; Jonkers, Jos; Matulonis, Ursula; Swisher, Elizabeth M; Konstantinopoulos, Panagiotis A; Chowdhury, Dipanjan (2018). Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas. Cell reports, 23(1), pp. 100-111. Cell Press 10.1016/j.celrep.2018.03.038

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

2211-1247

Publisher:

Cell Press

Language:

English

Submitter:

Achim Braun Parham

Date Deposited:

20 May 2019 16:26

Last Modified:

20 May 2019 16:26

Publisher DOI:

10.1016/j.celrep.2018.03.038

PubMed ID:

29617652

Uncontrolled Keywords:

BRCA2 mutations DSB repair RNA-DNA hybrids chemotherapeutic resistance microRNAs ovarian cancer replication fork single strand annealing

BORIS DOI:

10.7892/boris.127535

URI:

https://boris.unibe.ch/id/eprint/127535

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