Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas
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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-04-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718303802 |
| _version_ | 1818042515296616448 |
|---|---|
| author | Khyati Meghani Walker Fuchs Alexandre Detappe Pascal Drané Ewa Gogola Sven Rottenberg Jos Jonkers Ursula Matulonis Elizabeth M. Swisher Panagiotis A. Konstantinopoulos Dipanjan Chowdhury |
| author_facet | Khyati Meghani Walker Fuchs Alexandre Detappe Pascal Drané Ewa Gogola Sven Rottenberg Jos Jonkers Ursula Matulonis Elizabeth M. Swisher Panagiotis A. Konstantinopoulos Dipanjan Chowdhury |
| author_sort | Khyati Meghani |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-10T08:47:32Z |
| format | Article |
| id | doaj.art-b3d43fb7b6404de58fe771346b25edef |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T08:47:32Z |
| publishDate | 2018-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-b3d43fb7b6404de58fe771346b25edef2022-12-22T01:55:41ZengElsevierCell Reports2211-12472018-04-01231100111Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated CarcinomasKhyati Meghani0Walker Fuchs1Alexandre Detappe2Pascal Drané3Ewa Gogola4Sven Rottenberg5Jos Jonkers6Ursula Matulonis7Elizabeth M. Swisher8Panagiotis A. Konstantinopoulos9Dipanjan Chowdhury10Department of Radiation Oncology, Division of Radiation and Genome Stability, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USADepartment of Radiation Oncology, Division of Radiation and Genome Stability, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USADepartment of Radiation Oncology, Division of Radiation and Genome Stability, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USADivision of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the NetherlandsDivision 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, SwitzerlandDivision of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the NetherlandsDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USADivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Corresponding authorDepartment of Radiation Oncology, Division of Radiation and Genome Stability, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Corresponding authorSummary: 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 repairhttp://www.sciencedirect.com/science/article/pii/S2211124718303802 |
| spellingShingle | Khyati Meghani Walker Fuchs Alexandre Detappe Pascal Drané Ewa Gogola Sven Rottenberg Jos Jonkers Ursula Matulonis Elizabeth M. Swisher Panagiotis A. Konstantinopoulos Dipanjan Chowdhury Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas Cell Reports |
| title | Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas |
| title_full | Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas |
| title_fullStr | Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas |
| title_full_unstemmed | Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas |
| title_short | Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas |
| title_sort | multifaceted impact of microrna 493 5p on genome stabilizing pathways induces platinum and parp inhibitor resistance in brca2 mutated carcinomas |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718303802 |
| work_keys_str_mv | AT khyatimeghani multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas AT walkerfuchs multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas AT alexandredetappe multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas AT pascaldrane multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas AT ewagogola multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas AT svenrottenberg multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas AT josjonkers multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas AT ursulamatulonis multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas AT elizabethmswisher multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas AT panagiotisakonstantinopoulos multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas AT dipanjanchowdhury multifacetedimpactofmicrorna4935pongenomestabilizingpathwaysinducesplatinumandparpinhibitorresistanceinbrca2mutatedcarcinomas |