Abstract 2669: RRM2 inhibition synergizes with PARP inhibitor in ovarian cancer cells

Abstract

Abstract The use of Poly(ADP-ribose) polymerase inhibitors (PARPi) has been applied for the treatment of epithelial ovarian cancer (EOC) patients with homologous recombination (HR)-deficient disease, such as BRCA1/2 mutations. However, 40 - 70% of patients do not initially respond to PARPi in ovarian cancer with non-BRCA mutations, and acquired resistance has been demonstrated clinically. Ribonucleotide reductase (RNR, which consists of two RRM1 subunits and two RRM2 subunits) is the rate-limiting enzyme in the biosynthesis of dNTPs for DNA replication and DNA damage repair. As targeting RRM2 has been applied for many cancer therapies clinically or in clinical trials, this study hypothesizes that the inhibitory of RRM2 arguments PARPi potency against ovarian cancer. To this goal, this study evaluates the therapeutic effects of RRM2 inhibitor Osalmid (a resveratrol analog) alone or combined with PARPi by employing a panel of ovarian cancer cell lines using SRB assay. The effects on apoptosis and cell-cycle arrest were analyzed using flow cytometry. The cellular thermal shift assay was conducted to explore if Osalmid interacts with RRM2. DNA double strand break marker, ϒH2AX, was detected in compound-treated cells using Western blot. The results provide a new synthetic lethality by combining RRM2 inhibitor and PARPi. The combination induced apoptosis and caused the cell-cycle arrest. The results show that Osalmid binds to RRM2 directly. This study provides both a novel RRM2 inhibitor from a natural compound and a new understanding of the dNTP metabolic demands and may lead to urgently-needed strategies for the treatment of ovarian cancer. Citation Format: Chi-Wei Chen. RRM2 inhibition synergizes with PARP inhibitor in ovarian cancer cells [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 2669.