Abstract 6764: Comparative profiling of TEAD palmitoylation and YAP-TEAD protein-protein interaction inhibitors as combination agents with KRAS inhibitors

Abstract TEAD proteins are the transcriptional effectors of the Hippo pathway that bind coactivators YAP/TAZ to activate genes involved in cell survival, proliferation, and drug resistance. Deregulation of the Hippo pathway leading to increased TEAD activity occurs in multiple cancers, including as an adaptive resistance mechanism to targeted therapies. TEAD transcriptional signatures are elevated in KRAS inhibitor-resistant cell lines, and genome wide CRISPR screens have identified multiple hits in the Hippo pathway which sensitize or confer resistance to KRAS inhibitors. Therefore, targeting the YAP/TAZ-TEAD axis has the potential to inhibit tumor growth as a monotherapy or combination strategy across diverse indications. TEAD inhibitor modalities being investigated clinically include TEAD “central pocket” palmitoylation inhibitors (CPIs) and YAP-TEAD protein-protein interaction inhibitors (PPIs). However, limited data exist on how targeting TEAD with these different classes of inhibitors compare in combination studies. We profiled the activity of a TEAD CPI and PPI alone and as combination agents with KRASG12C and KRASG12D inhibitors, assessing effects on TEAD-dependent transcription, proliferation, and tumor growth inhibition. In long-term in vitro outgrowth studies in six KRASG12C and KRASG12D cell lines, the TEAD PPI demonstrated increased growth inhibition compared to the CPI when combined with KRAS inhibitors. Additionally, the PPI re-sensitized KRASG12C-mutant NCI-H2122 cells resistant to AZD4625, a KRASG12C-selective inhibitor. Combination efficacy was observed across KRAS-mutant but not WT lines, confirming on-target activity of dual TEAD and MAPK pathway suppression. Mechanistically, the PPI suppressed TEAD-dependent transcription to a greater extent than the CPI in vitro, while reduced MAPK signaling was driven by KRAS inhibitors and not further enhanced by TEAD inhibition. Given the differences between CPI and PPI activity in vitro, combination efficacy was evaluated in vivo in three KRAS-mutant tumor models. In contrast to the in vitro results, CPI and PPIs drove equivalent regression of NCI-H2122 NSCLC xenografts when combined with the KRASG12C inhibitor sotorasib, followed by similar outgrowth once dosing was stopped. However, the robust combination efficacy observed in vitro did not translate to significant tumor growth inhibition with either TEAD modality in two KRASG12D-mutant pancreatic models, Panc04.03 and Panc10.05. Collectively, these findings suggest that while differential activity was observed between TEAD CPI and PPIs in vitro, the two modalities drove similar therapeutic benefit in vivo when combined with KRAS inhibitors. Careful exploration of the long-term benefit of TEAD and KRAS inhibitor combinations is warranted due to the disconnect between in vitro and in vivo data. Citation Format: Danielle J. Sanchez, Jacob A. Gordon, Cynthia Xu, Alex Koers, Sarah Ross, James E. Brownell, Simon T. Barry, Carla P. Martins. Comparative profiling of TEAD palmitoylation and YAP-TEAD protein-protein interaction inhibitors as combination agents with KRAS inhibitors 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 6764.