UC San Diego

Abstract High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the U.S. and is marked by resistance to chemo- and immunotherapy. Although focal adhesion kinases (FAK and PYK2) are known to induce tumor microenvironment immunosuppression, their role in altering tumor-cell major histocompatibility complex class-II (MHC-II) presentation requires further investigation. HGSOC tumors have few mutations but frequently show FAK amplification (∼75%). Notably, elevated MHC-II expression correlates with longer progression-free survival in recurrent HGSOC, likely through enhanced CD4+ T-cell activation and improved anti-tumor immunity. Flow cytometry analysis revealed that ATP competitive small molecule inhibition of FAK kinase activity (FAKi) increases MHC-II antigen presentation in vitro and in vivo. Targeted FAK protein degradation following treatment with a FAK proteolysis targeting chimera (FAK-PROTAC) produced a similar effect. In a syngeneic orthotopic mouse model, FAK depletion induced MHC-II to levels comparable to kinase-dead FAK, consistent with the loss of FAK activity in promoting tumor MHC-II expression. As ovarian tumor cells also express the FAK-related homolog PYK2, CRISPR was employed to selectively inactivate FAK and or PYK2 expression in human OVCAR3, murine KMF, and murine HGS2 ovarian tumor models. Notably, loss of FAK, but not PYK2, resulted in enhanced MHC-II presentation in these cells. As tumor cell treatment with a dual FAK-PYK2 inhibitor or PROTAC that targets FAK and PYK2 does not induce MHC-II expression as does selective loss of FAK, our results support a distinct immunogenic role for PYK2 in ovarian tumor cells. Ongoing studies are evaluating PYK2 mechanism of action upon FAK inhibition and the regulation of CIITA (class II, major histocompatibility complex, transactivator) transcription. Collectively, our findings suggest roles for FAK-specific inhibitors that may potentiate MHC-II-related adaptive immune responses as a therapeutic strategy for advanced ovarian cancer. Citation Format: Terrance James Haanen, Xiao Lei Chen, David D. Schlaepfer., . Opposing control of MHC-II antigen presentation by FAK and PYK2: Implications for therapeutic intervention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1603.