Abstract B022: TEAD inhibition overcomes YAP/TAZ-driven resistance to RAS(ON) inhibitors

Abstract Acquired resistance poses a significant challenge to the long-term efficacy of RAS inhibitors in clinical settings (Awad et al, 2021). Genome-wide CRISPR screening efforts, conducted by us and others in the field, have identified key components of the Hippo pathway as major mediators of resistance to RAS inhibitors (Mukhopadhyay et al., 2023, Edwards et al., 2023). Specifically, the oncogenic transcriptional co-regulators YAP and TAZ, which require binding to the TEAD transcription factors to elicit their activity, have emerged as pivotal players in resistance mechanisms to MAPK pathway targeted therapies. In this work, we demonstrate that YAP overexpression is a driver of resistance to RAS(ON) multi-selective and RAS(ON) G12C-selective inhibitors. The YAP transcriptional signature is elevated in cells with acquired resistance to RAS(ON) inhibitors, and combination with TEAD inhibitors enhances their sensitivity to RAS(ON) inhibition. Notably, phosphoproteomics and imaging studies revealed that the YAP cytoplasmic retention mark is reduced upon treatment of cancer cells with RAS(ON) multi-selective inhibitor, leading to the translocation of YAP to the nucleus and its subsequent activation. Furthermore, a pan-TEAD inhibitor exhibits a high degree of synergy with RAS(ON) inhibitors in a panel of KRAS mutant cell lines in vitro. We are currently investigating the combination of RAS(ON) and TEAD inhibitors in vivo. Our studies support further investigation of combination strategies using RAS(ON) and TEAD inhibitors to mitigate the emergence of persister cells and overcome resistance to monotherapy. Citation Format: Vidyasiri Vemulapalli, Phuong Dinh, Mariela Moreno Ayala, Zheng Zhang, Mark Labrecque, Ida Aronchik, Jingjing Jiang, Mallika Singh, Elsa Quintana, Caroline Weller, David Wildes. TEAD inhibition overcomes YAP/TAZ-driven resistance to RAS(ON) inhibitors abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B022.