Abstract MIP-047: INHIBITION OF POLY ADP–RIBOSE POLYMERASE (PARP) IN OVARIAN CANCER CELLS ENRICHES FOR CD133 AND CD117 POSITIVE POPULATIONS

Abstract

Abstract Keywords: chemoresistance, cancer stem cells (CSC), DNA repair pathways, PARP inhibition INTRODUCTION: Ovarian cancer (OvCa) is the most lethal gynecologic malignancy as women commonly present with metastatic disease that ultimately develops chemotherapy resistance. The development of OvCa has been linked to alterations in DNA repair pathways and the poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor olaparib has demonstrated antitumor activity and is an FDA approved monotherapy for the treatment of recurrent OvCa in patients with a germline BRCA mutations. Despite promising response rates, not all patients derive benefit, and the majority develop resistance to this therapy that is poorly understood. We hypothesized that ultimate resistance to olaparib is in part mediated by small populations of cancer stem cells (CSCs) that are unaffected by olaparib therapy and may promote tumor resurgence. METHODS: UWB1.289 (BRCA1 mutated), UWB1.289 (WT), OVCAR4 (WT), and OVCAR3 (WT) cell lines and primary cell lines derived from serous OvCa obtained with IRB approval were treated in vitro with 0.1 μM, 1 μM and 10 μM olaparib for 7 days. We assessed cell viability and CSC marker expression (CD133 and CD117) via flow cytometric analysis, and sphere forming capacity via extreme limiting dilution assay (ELDA). RESULTS: Consecutive treatment over 7 days with olaparib decreased the viability of the non–sorted tumor cell population relative to the vehicle control treated cells. Despite the decrease in total cell number, the relative frequency of CD133+ and CD117+ cells increased (all lines p <0.05) in response to treatment with olaparib. This shift was not observed in vehicle treated cells. The increase in CD133+ and CD117+ cell frequency in response to olaparib was not different in the BRCA1 mutant line when compared to the BRCA1 wild type lines. ELDA revealed an increase in the frequency of sphere formation following olaparib treatment relative to that observed with vehicle treated cells, though mutation status did not impact this frequency. CONCLUSIONS: These results suggest that olaparib may enrich for CSC populations that could contribute to resistance and recurrence. These data expose a potential resistance mechanism to olaparib therapy that is in part independent of BRCA mutation status. Citation Format: Chiara Bellio, Rosemary Foster, Whitfield B. Growdon Panagiotis Konstantinopoulos, and Bo R. Rueda. INHIBITION OF POLY ADP–RIBOSE POLYMERASE (PARP) IN OVARIAN CANCER CELLS ENRICHES FOR CD133 AND CD117 POSITIVE POPULATIONS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-047.