Abstract B009: TEAD inhibition overcomes YAP1/TAZ-driven resistance to RAS inhibitors in KRASG12C-mutant cancers

Abstract

Abstract Activated mutants of KRAS comprise the major oncogenic drivers in lung (LAC), colorectal (CRC), and pancreatic ductal (PDAC) adenocarcinoma. Recent success in covalently targeting one KRAS mutant (KRASG12C) led to FDA approval of the first anti-KRAS therapy (G12Ci). However, both primary and treatment-induced acquired resistance to G12Ci have been observed. While analyses of relapsed patients have identified reactivation of the key KRAS effector signaling network as a driver of resistance, the mechanisms in ~50% of patients are not known. To identify potential resistance mechanisms, we applied a CRISPR-Cas9 loss-of-function screen targeting the druggable genome. In addition to genes discovered recently in relapsed patients (e.g., PTEN, NF1), we also identified loss of multiple components of the Hippo tumor suppressor pathway as drivers of G12Ci resistance (NF2, LATS1/2, TAOK1/2 and STK3/4). We therefore determined if activation of the functionally related transcriptional co-activators, YAP1 and TAZ, normally inhibited by Hippo signaling, can drive resistance to G12Ci. We first determined that ectopic expression of constitutively activated YAP1/TAZ was sufficient to impair the anti-proliferative and pro-apoptotic effects of G12Ci treatment in KRASG12C-mutant LAC, CRC, and PDAC cell lines. Conversely, genetic suppression of YAP1/TAZ enhanced G12Ci sensitivity. YAP1/TAZ requires association with TEAD and other transcription factors to regulate transcription. We determined that YAP1/TAZ mutants deficient in TEAD binding failed to drive resistance to G12Ci treatment. Further supporting a role for TEAD, both overexpression of a TEAD dominant negative mutant and treatment with pan-TEAD pharmacological inhibitors phenocopied the effects of YAP1/TAZ genetic suppression and sensitized KRASG12C mutant cancer cells to G12Ci. Finally, transcriptional analyses support a model where YAP1/TAZ-TEAD overcomes KRASG12C addiction by restoring a subset of KRAS-dependent gene transcription. In summary, our observations support YAP1/TAZ-TEAD signaling as a novel driver of resistance to KRAS inhibition and support the use of TEAD inhibitors to enhance the anti-tumor efficacy of KRAS-targeted therapies. Citation Format: Alexander C. Edwards, Clint A. Stalnecker, Alexis J. Morales, Khalilah E. Taylor, Jill Hallin, Peter Olson, Tracy T. Tang, Lars Engstrom, Leonard Post, James G. Christensen, Adrienne D. Cox, Channing J. Der. TEAD inhibition overcomes YAP1/TAZ-driven resistance to RAS inhibitors in KRASG12C-mutant cancers [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B009.