Abstract A133: Target clear cell ovarian cancers with ARID1A loss by combination inhibition of BRD4 and ATR

Abstract Background: Clear cell ovarian cancer (CCOC) is often resistant to standard chemotherapy and has limited treatment options in the advanced or recurrent setting. ARID1A is the most prevalent mutation, with approximately 50% of all CCOC harboring this mutation. ARID1A, a member of the SWI/SNF family, regulates transcription and has a major role in the repair of DNA lesions, directly facilitating DNA accessibility on the chromatin or indirectly by facilitating the functions of DNA repair proteins. We propose that CCOCs unique genomic alterations (e.g., ARID1A frameshift or nonsense mutations) will increase dependency on chromatin remodeling and DNA repair (e.g., ATR/CHK1/WEE1) pathways for survival. We hypothesize that combination of low-dose small-molecule inhibitors of the BET family (BRD4i) and the DNA damage repair pathway (ATR/CHK1/WEE1), will especially target ARID1A mutant cancer cells promoting mitotic catastrophe, apoptosis, and tumor regression, sparing normal cells. Method: Use a small size drug screen, we tested and compared drugs’ efficacy in ARID1A mutant cells with wildtype lines. The efficacy of BRD4i combination with either ATRi or WEE1i were evaluated in ARID1A mutant/wildtype lines, and also knockdown or knockout cells compared with isogenic parental lines. The drugs combination affecting the transcription regulation, cell cycle, homologous recombination, apoptosis, and DNA damage were investigated. A CCOC preclinical drug development patient-derived xenograft (PDX) platform was established and drugs’ combinations were evaluated in ARID1A mutant and ARID1A wild-type (ARID1A MUT and ARID1A WT) PDX models. Results: Through the small size of drug screen, we identified that BRD4i, ATRi and WEE1i are more effective in ARID1A mutant cells comparing to that in wildtype lines. Low-dose combination of BRD4i with DNA damage repair inhibitors, ATRi/WEE1i (BDR4i-ATRi or BRD4i-WEE1i), were synergistic in decreasing survival and colony formation in ARID1A MUT cells compared to ARID1A WT. Both combinations showed significant tumor regression and increased overall survival compared to standard chemotherapy or monotherapy in several ARID1A MUT PDX models but minimal in an ARID1A WT PDXs. Among BRD4i-DDRi combinations, BRD4i-ATRi is superior to BRD4i-WEE1i in terms of antitumor effect and drug tolerability. BRD4i-ATRi caused a robust G1 arrest. The BRD4i-ATRi treatment defects homologous recombination and leads to an increase in DNA double-strand breaks and cell apoptosis in the ARID1A MUT or knockout cells. Conclusion: Our studies identify a novel drug combination targeting a genetic alteration (e.g., ARID1A) common in CCOC that is highly effective and tolerable. BRD4i in combination with ATRi or WEE1i was synergistic in vitro in ARID1A MUT models. Using our novel CCOC drug development PDX platform, we demonstrated that BRD4i-ATRi combination therapy is more effective than standard chemotherapy or monotherapy alone with acceptable toxicity in ARID1A MUTPDXs. Citation Format: Yasuto Kinose, Haineng Xu, Hyoung Kim, Xiaolei Wang, Sushil Kumar, Xiaoyin Shan, Erin George, Sergey Medvedev, Amaryllis Ortiz, Sarah Gitto, Margaret Whicker, Kurt D'Andrea, Bradley Wubbenhorst, Dorothy Hallberg, Mark O'Connor, Lauren Schwartz, Wei-Ting Hwang, Katherine L. Nathanson, Gordon Mills, Victor E. Velculescu, Tian-Li Wang, Eric Brown, Ronny Drapkin, Fiona Simpkins. Target clear cell ovarian cancers with ARID1A loss by combination inhibition of BRD4 and ATR [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A133.