Abstract 1850: Co-targeting EZH2 and TEAD elicits apoptosis through tumor-intrinsic innate immune signaling in Hippo pathway-mutated cancers.

Abstract TEA/TEF-domain [TEAD] inhibitors are being evaluated in clinical trials for cancers with alterations in the Hippo pathway including mesothelioma. We recently developed and showcased the potency of TEAD palmitoylation inhibitors MYF-03-69 and MYF-03-176 in mesothelioma cell lines. However, TEAD inhibition results in cell cycle arrest in cell line models with Hippo pathway alterations without inducing cell death, potentially limiting their long-term clinical efficacy. Using a genome-wide CRISPR/Cas9 screen, we identified EZH2 as a critical modulator of the cellular response to TEAD inhibition. Compared to single agent treatments, EZH2i/TEADi robustly triggered apoptosis and suppressed the growth of Hippo-mutated cells in vitro and in vivo. Mechanistically, EZH2i/TEADi-treated cells exhibited heightened activation of tumor-intrinsic innate immune signaling which resulted in DNA damage and subsequent apoptosis. Taken together, we propose this novel combinatorial strategy as a potential approach to enhancing the anti-tumor efficacy of single agent TEAD targeting therapies in Hippo pathway altered tumors. Citation Format: Antja-Voy Hartley, Mustafa Al-Dulaimi, Navin R. Mahadevan, Pinar Eser, William W. Feng, Tran Thai, Jeanelle A. Tsai, Caitlyn Weston, Nicholas Tourtillot, Matthew Booker, Joseph Kulesza, Zhaorong Li, Elizabeth Cohen, Sean Lenahan, Choudhury Fabliha Yusuf, Abeba Teshager, Prafulla C. Gokhale, Shweta Kukreja, Sonsoles Liria Veiga, Rong Li, Xintao Qiu, Henry W. Long, Michael Y. Tolstorukov, Matthew G. Oser, Nathanael S. Gray, David A. Barbie, Pasi A. Janne. Co-targeting EZH2 and TEAD elicits apoptosis through tumor-intrinsic innate immune signaling in Hippo pathway-mutated cancers [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 1850.