Abstract SY27-01: Combination therapies to enhance RAS inhibitor efficacy: Thinking outside the box

Abstract The perception that KRAS is undruggable was shattered with the recent approval of two KRAS G12C inhibitors for the treatment of non-small cell lung and colorectal cancers. This success has spurred extensive drug development efforts, with currently over 60 RAS inhibitors targeting essentially all RAS mutations under evaluation in over 170 active clinical trials. However, limited objective response rates and median overall survival highlight the impact of intrinsic and acquired resistance in limiting clinical efficacy. Preclinical experimental studies and genetic analyses of relapsed patients have identified a diverse spectrum of genetic, signaling and cell state mechanisms that drive resistance. Our studies focus on the most KRAS-addicted cancer type, pancreatic ductal adenocarcinoma. We validated the ERK MAPK cascade as a central driver of RAS inhibitor resistance and the MYC transcription factor as the major mechanistic basis of ERK-dependent cancer growth. We also validated the Hippo YAP/TAZ-TEAD and KEAP1-NRF2 transcriptional programs as key contributors to RAS inhibitor resistance. To define the mechanistic basis for resistance, we have profiled ERK, MYC, TEAD and KEAP1-NRF2 regulated transcription and phosphoprotein programs and applied CRISPR-based loss-of-function screens to identify molecular mechanisms of RAS inhibitor resistance. Our studies validated combination strategies focused on orthogonal processes distinct from the RAS signaling network. These include inhibition of the TEAD transcription factor, the AXL receptor tyrosine kinase, and the PRMT5 protein arginine methyltransferase. We also identified two approaches targeting mitochondrial function, blocking glutamine-dependent processes or activation of the ClpP mitochondrial protease. In summary, our studies support the potential therapeutic value of combinations that target processes orthogonal to but converge on the RAS signaling network. Citation Format: Channing J. Der. Combination therapies to enhance RAS inhibitor efficacy: Thinking outside the box [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY27-01.