Abstract 829: <i>ITGAV</i> is a targetable vulnerability in epithelial ovarian cancer

Abstract Ovarian cancer is a lethal heterogenous disease that is typically diagnosed at late stages. In high-grade serous ovarian carcinoma (HGSOC), the most common subtype, PARP inhibitors and chemotherapy are standard of care. Although HGSOC patients are responsive to these therapies, resistance develops and patients invariably relapse. Alterations in genes within the phosphoinositide 3-kinase (PI3K) and AKT network are highly prevalent. Although specific PI3K and AKT small molecule inhibitors have been developed and clinically evaluated, to date none have been approved for clinical use in ovarian cancer patients. To identify collateral druggable vulnerabilities to AKT hyperactivation and develop novel combination therapies in HGSOC, we have performed a CRISPR-based genome-wide synthetic lethal screen. The goal is to identify genes that upon genetic knockout transform a cytostatic cellular response to PI3Ki/AKTi to a cytotoxic one. Using this platform, we have identified genes that regulate integrin signaling as a major mechanism of synthetic lethality against the PI3Ki pictilisib and the AKTi capivasertib. ITGAV, encoding the integrin subunit αV, was a significant dropout against both kinase inhibitors. Pharmacological targeting of integrin αV synergized with pictilisib and capivasertib to induce apoptotic cell death in multiple cell line models of ovarian cancer, as well as patient-derived organoids. Combined PI3K/AKT and integrin αV inhibition induced DNA damage and cell cycle arrest. The mechanisms underlying induction of DNA damage and cell death in response to combination treatment are currently under investigation. The ultimate goal is to bring this combination treatment approach to HGSOC patients and shed new light on mechanisms of resistance to PI3K/AKT pathway inhibitors in ovarian cancer. Citation Format: Gilbert K. Salloum. ITGAV is a targetable vulnerability in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 829.