Abstract 5507: A potential combinatorial treatment strategy to overcome olaparib resistance in high-grade ovarian cancer

Abstract

Abstract PARP1 inhibitors have evolved the treatment of BRCA1/2-mutated high-grade serous ovarian cancer. However, its resistance is frequently observed. In our initial combinatorial drug screening, OSU-03012 (AR-12) appeared as a promising drug to be combined with PARP inhibitor Olaparib in multiple ovarian cancer cell lines, regardless of BRCA mutation status. OSU-03012 is designed as an orphan drug with anti-microbial activity. It has also shown cell-context-dependent anti-cancer activity. Using imaging-based high-throughput drug sensitivity analysis, we found that OSU-03012 and BX-912, while both classified as 3-Phosphoinositide Dependent Protein Kinase 1 (PDK-1) inhibitors, not only differed in their synergistic effect together with Olaparib, also caused distinct phenotypic changes in ovarian cancer cells. Cell senescence was observed in BX-912 but not OSU-03012 treatment, alone or together with Olaparib. Recently, dihydroorotate dehydrogenase (DHODH) has been identified as a secondary target of OSU-03012, which explains its anti-cancer activity by regulating nucleotide metabolism and thus affecting DNA repair. However, in our study, OSU-03012 did not similarly affect cell viability and phenotype on ovarian cancer cell lines as a DHODH inhibitor BAY2402234. Interestingly, compared to BX-912 and BAY2402234, OSU-03012 showed higher selectivity on ovarian cancer cell lines over normal epithelial carrying BRCA and TP53 mutations; it also exhibited reduced toxicity on a human fibroblast cell line. We are further clarifying the putative targets of OSU-03012 using thermal proteome profiling. To investigate the molecular evidence of OSU-03012 for treating ovarian cancer, we performed a differential gene expression analysis using Genomics of Drug Sensitivity in Cancer (GDSC) database. All ovarian cancer cell lines included in GDSC drug screening are classified as Olaparib- or OSU-03012-sensitive/insensitive, based on the respective IC50 threshold. We found that OSU-03012 sensitivity is positively associated with several known genes regulating ovarian cancer progression, such as LUM and COL3A1, as well as genes (e.g., PTPRZ1) that are associated with Olaparib insensitivity in this analysis. Interestingly, angiogenesis signatures were found to be enriched in both Olaparib and OSU-03012-sensitive cancer cell lines. We are currently establishing a cancer-vascular cell system in a microfluidic setting to study how such combinatorial drug treatment would connect to tumor microenvironment remodeling. Altogether, we identified a potential non-cancer drug for ovarian cancer treatment and to overcome Olaparib resistance. A multidisciplinary approach highlights the importance of drug target profiling and sensitivity signatures scoring to improve treatment stratification. Citation Format: Jie Bao, Eva Daniela Mendoza Ortiz, Jessica Agudelo, Roman Filimonov, Anniina Färkkilä, Jing Tang. A potential combinatorial treatment strategy to overcome olaparib resistance in high-grade ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5507.