Abstract B060: Dual blockade of BRD4 and the ATR/WEE1 pathway exploits ARID1A loss in clear cell ovarian cancer

Abstract

Abstract Clear Cell Ovarian Cancer (CCOC) is one of the most challenging subtypes of ovarian cancer to treat as advanced stages are often chemo-resistant compared to the more common high-grade serous ovarian cancer (HGSOC). Limited treatment options are available for this devastating disease. Understanding the resistance mechanism and identifying effective therapeutic options for CCOC are clearly needed. Exploiting genetic alterations common in CCOC, such as ARID1A, is a rational strategy for combination therapies. ARID1A, an epigenetic tumor suppressor, is the most common genetic mutation in CCOC, with about 50% of CCOC demonstrating loss of ARID1A. ARID1A regulates the transcription of specific genes (e.g. c-myc) by altering the chromatin structure. We hypothesize that ARID1A loss increases CCOC cell dependency on chromatin remodeling and DNA repair pathways for survival. Through a drug screen, BET inhibitors and DNA damage response inhibitors were the most active monotherapies in ARID1A mutant CCOC. However, monotherapy efficacy needs to be further improved. We demonstrate in our study that the combination of BRD4 inhibitor (BRD4i) with DNA damage response (DDR) inhibitors (ATR or WEE1 inhibitors; e.g. BRD4i-ATRi) were synergistic at low doses leading to decreased survival, and colony formation in an ARID1A dependent manner. Combination BRD4i-ATRi caused significant tumor regression and increased overall survival in ARID1AMUT not ARID1AWT patient-derived xenograft (PDX) models. Combination BRD4i-ATRi significantly increased gH2AX, and decreased RAD51 foci and BRCA1 expression suggesting loss in the ability to repair DNA double-strand-breaks by homologous recombination (HR), more so than with monotherapy in ARID1AMUT cells. These studies demonstrate BRD4i-ATRi is an effective treatment strategy that capitalizes on synthetic lethality with ARID1A loss in CCOC warranting further study. Citation Format: Yasuto Kinose, Haineng Xu, Sushil Kumar, Hyoung Kim, Sergey Medvedev, Xiaolei Wang, Erin George, Xiaoyin Shan, Sarah Gitto, Kurt D'Andrea, Bradley Wubbenhorst, Margaret Whicker, Dorothy Hallberg, Lauren Schwartz, Katherine L Nathanson, Gordon Mills, Victor E Velculescu, Tian-Li Wang, Eric Brown, Ronny Drapkin, Fiona Simpkins. Dual blockade of BRD4 and the ATR/WEE1 pathway exploits ARID1A loss in clear cell ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B060.