Abstract NT-100: PARPI-INDUCED ALDH1A1 EXPRESSION CONTRIBUTES TO PARPI RESISTANCE IN OVARIAN CANCER CELLS

Abstract

Abstract Ovarian cancer (OC) is one of the most lethal female malignancy which accounts for just 2.5% of female cancer cases but 5% of deaths because of low survival. 90% of OC are epithelial ovarian cancer (EOC), with an overall 5-year relative survival rate of 47% and only 29% for patients diagnosed with distant-stage. 20% of OC cases are estimated to be due to inherited mutations that confer elevated risk, especially cancer susceptibility genes BRCA1 and BRCA2. PARP inhibitors (PARPi) are novel and promising cancer-targeted drugs. PAPRi are approved by FDA for clinical treatment of advanced EOC patients with BRCA1/2 gene mutation. However, patients gradually gained resistance to PARPi with continuously increased recurrence rate (>90%). Thus, understanding the mechanism underlying PARPi resistance is an urgent need for improving the PARPi efficacy. Aldehyde dehydrogenase (ALDH) activity is considered as a cancer stem cell (CSC) marker and also relative to drug resistance. However, the relationship between ALDH activity and PAPPi resistance remains unclear. In this study, we generated two olaparib-resistant EOC cell lines by continuously treating BRCA2-mutated PEO1 and Kuramochi cell lines for 6 months, and found that these resistant cell lines exhibited higher ALDH activity compared to their corresponding parent cell lines. In addition, short-term treatment of PEO1 and Kuramochi cells with olaparib (7 days) also increased the ALDH+ cell population in these cells, and olaparib-induced ALDH--to-ALDH+ conversion contributed to the expansion of the ALDH+ cell population after olaparib treatment. qRT-PCR analysis demonstrated that ALDH1A1 is the major gene in the ALDH gene family that was induced by olaparib. Overexpression of ALDH1A1 increased olaparib resistance in a panel of EOC cells lines including both BRCA2-muated and BRCA2-wild type cell lines. In summary, our data indicate that olaparib is able to induce ALDH1A1 gene expression, which results in the enhanced ALDH activity. The enhanced ALDH activity can contribute to olaparib resistance in BRCA2-mutated EOC cells. Citation Format: Lu Liu, Shurui Cai, Chunhua Han, Ananya Benerjee, Dayong Wu, Tiantian Cui, Guozhen Xie, Yanfang Zheng, and Qi-En Wang. PARPI-INDUCED ALDH1A1 EXPRESSION CONTRIBUTES TO PARPI RESISTANCE IN OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-100.