Abstract LB-329: MicroRNA profiling to identify novel determinants of platinum resistance in BRCA1/2-mutated high-grade serous ovarian cancer
Authors: Meghani Khyati , Gogola Ewa , Rottenberg Sven , Jonkers Jos , Matulonis Ursula , Swisher Elizabeth , Konstantinopoulos Panagiotis , Chowdhury Dipanjan 
Published: July 2017

Ovarian cancer is the fifth leading cause of mortality in women and the most lethal of all gynecologic tumors. Patients with high grade serous ovarian carcinoma (HGSOC) have poor prognosis due to a combination of factors including lack of early detection and failure of therapeutic regimens. Approximately 50% of all ovarian tumors have germline/somatic mutations or epigenetic alterations in genes making up the homologous recombination (HR) pathway. The resultant “BRCAness” phenotype pre-disposes these tumors to an improved response from current ovarian cancer therapies i.e. platinum therapy and PARP inhibitors. Despite the predicted synthetic lethality, a majority of patients with recurrent ovarian cancer eventually develop resistance. A detailed understanding of clinically relevant mechanisms of chemotherapy resistance is an important step in improving disease outcomes.

To systematically identify microRNA (miRNA) mediators of chemo-resistance in HGSOC, we performed small RNA sequencing of 38 BRCA mutated tumors with known response to platinum chemotherapy and identified three miRNA’s: miR-139-5p, miR-493-5p and miR-494-3p that were significantly overexpressed in platinum resistant compared to the platinum sensitive tumors. Overexpression of these candidate miRNA’s was associated with worse overall outcome among BRCA1/2-mutated tumors in the TCGA dataset. Interestingly, overexpression of miR-493-5p only correlated with poor progression free survival in BRCA2 mutant tumors and not BRCA1 mutant tumors. Importantly, overexpression of miR-493-5p was also identified in 13 out of 40 olaparib resistant tumors in KB2P BRCA2 deficient mouse models. Additionally, overexpression of miR-493-5p in BRCA2 mutated HGSOC cell-lines induced resistance to cisplatin and olaparib in vitro. Mechanistically, resistance mediated by miR-493-5p was not associated with restoration of HR (as evaluated by restoration of Rad51 foci) but was rather related to replication fork stabilization. Identification of specific targets of miR-493-5p is currently underway. In summary, overexpression of miR-493-5p may be a novel mechanism of resistance to platinum and PARP-inhibitors in BRCA2-mutated ovarian cancers and may serve as a biomarker of response to these agents in BRCA2 mutated ovarian tumors. Inhibition of miR-493-5p may be a novel strategy to resensitize chemo-resistant BRCA2 mutated tumors to platinum therapy and PARP-inhibitors.

Citation Format: Khyati Meghani, Ewa Gogola, Sven Rottenberg, Jos Jonkers, Ursula Matulonis, Elizabeth Swisher, Panagiotis Konstantinopoulos, Dipanjan Chowdhury. MicroRNA profiling to identify novel determinants of platinum resistance in BRCA1/2-mutated high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-329. doi:10.1158/1538-7445.AM2017-LB-329