Abstract IA002: Drugging RAS: What a long, strange trip it’s been

Abstract Once considered “undruggable”, KRAS has become an attractive therapeutic target with the recent approval of two KRAS G12C inhibitors for the treatment of non-small cell lung and colorectal cancers, marking a major milestone in cancer drug discovery. This success has catalyzed extensive drug development efforts, with currently over 65 RAS inhibitors targeting essentially all RAS mutations under evaluation in over 150 active clinical trials. However, limited objective response rates (<40%) and median overall survival 6.9 to 14.5 months) underscore the impact of both intrinsic and acquired resistance clinical efficacy. Genetic analyses of relapsed patients and experimental studies have revealed a remarkable diverse set of genetic, signaling and cell state mechansisms that drive resistance. Our research focuses on pancreatic cancer, the most KRAS-addicted cancer type. We established the ERK MAPK cascade as a central driver of RAS inhibitor resistance, with the MYC transcription factor the major driver of ERK-dependent cancer growth. In addition, we have validated the Hippo YAP/TAZ-TEAD and KEAP1-NRF2 transcriptional programs as key contributors to resistance. To define the mechanistic basis for resistance, we have profiled ERK, MYC, TEAD and KEAP1-NRF2 regulated transcriptomes and phosphoproteomes and performed CRISPR-based loss-of-function screens to identify modulators of RAS inhibitor sensitivity. Our studies we have revealed multiple combination strategies, including inhibition of TEAD, AXL receptor tyrosine kinase and PRMT5 protein arginine methyltransferase or activation of the ClpP mitochondrial protease that significantly enhance RAS inhibitor efficacy. Citation Format: Channing J. Der. Drugging RAS: What a long, strange trip it’s been [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr IA002.