Abstract LB288: Determination of the MYC- and TEAD-dependent transcriptome in pancreatic cancer

Abstract Both intrinsic and acquired resistance limit the depth and duration of response to all clinically evaluated anti-KRAS therapies. Genetic resistance mechanisms, identified in nearly half of relapsed patients, include acquisition of mutations that effectively restore KRAS-dependent activities. Reported non-genetic mechanisms include signaling and transcriptional activities that support epithelial-to-mesenchymal transition (EMT) or transition to cancer subtypes less responsive to KRAS inhibition. We recently reported MYC amplification and TEAD-dependent transcriptional activation by YAP as drivers of resistance to the multi-RAS inhibitor RMC-7977 (RASmulti), the preclinical analog of RMC-6236. Importantly, we showed that cells resistant to RASmulti that harbor amplified MYC could be re-sensitized to RAS inhibition by co-treatment with TEAD inhibitors. These studies motivated us to define the MYC- and TEAD-dependent transcriptional profiles in KRAS-mutant pancreatic adenocarcinoma (PDAC) cells. We knocked down MYC using siRNA in a panel of eight human PDAC cell lines to derive the MYC-dependent transcriptome. We found 3,010 MYC-dependent genes, 36% of which support oncogenic KRAS signaling through ERK. To determine the TEAD-dependent transcriptome, we treated a panel of three sets of paired naïve and RASmulti-resistant KPC cell lines, derived from an autochthonous mouse model of PDAC, and of six human KRAS-mutant PDAC cell lines with the TEAD inhibitor IAG933, with RMC-7977, or with the combination. We found 3,865 TEAD-dependent genes in mouse cells and 3,590 TEAD-dependent genes in human cells. We found co-regulated RAS, MYC, and TEAD gene transcriptional networks enriched for essential genes that support cell cycle progression. We also found distinct gene clusters regulated by each protein that support distinct molecular functions, such as protein biosynthesis, RHO GTPases, and immune signaling. Importantly, combined inhibition of TEAD and RAS led to a more robust downregulation of essential genes than either single treatment. Proteomic profiling of PDAC cell lines with acquired resistance to RMC-7977 showed upregulation of TEAD-dependent gene products, supporting TEAD activation as a non-genetic mechanism of acquired resistance. Together, our findings expand the role of MYC and TEAD in supporting PDAC cell growth and resistance to RAS inhibition and provide rationale for further evaluation of combination therapeutic strategies to limit resistance. Citation Format: Brandon L. Mouery, Priya S. Hibshman, A Cole Edwards, Ryan D. Mouery, Runying Yang, Jeff A. Klomp, Angie L. Mordant, Thomas S. Webb, Aurora Cabrera, Laura E. Herring, Adrienne D. Cox, Timour Baslan, Channing J. Der, Clint A. Stalnecker. Determination of the MYC- and TEAD-dependent transcriptome in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB288.