Abstract B043: Multi-Omic mapping reveals stress-MAPK dependent mechanisms of resistance to KRASG12C inhibitors in colorectal cancer

Abstract KRAS mutations are found in 35%–45% of colorectal cancers, heavily influencing the prognosis and response to treatment. While KRASG12C inhibitors have shown promising efficacy in non–small cell lung cancer, their impact in colorectal cancer has been modest, underscoring the need to understand tissue-specific mechanisms of adaptive resistance. To address this, we integrated global phosphoproteomics, multiplex inhibitor bead based kinome profiling, and high-throughput kinase activity mapping to define signaling rewiring following KRASG12C inhibition across genetically diverse KRASG12C/APC mutant colorectal cancer cells. After KRASG12C inhibition, stress responsive MAPKs, including p38 and JNK were activated. In addition, transcriptional analysis revealed coordinated induction of interferon response genes, TGFs, and ion transporters, as well as repression of key amino acid transporters reflecting widespread transcriptional reprogramming. To identify functional dependencies underlying these adaptations, we developed a paralog-targeted Cas12a dual-guide kinome library. Screens in KRASG12C mutant colorectal cancer cells representing the CMS3 (RW7213) and CMS4 (SW837) molecular subtypes uncovered collateral dependencies on stress MAPK components (MAPK11/12/14, MAP3K4/7/8), NF-κB pathway kinases, and the WNK–SPAK–STK39 signaling module. We hypothesize that alterations in inflammatory and mesenchymal ligands, as well as cellular osmotic stress, all converge to activate these stress MAPKs. Ongoing studies are assessing the mechanism of stress MAPK activation by the multiple transcriptional adaptations to KRAS inhibition. We are also investigating the impact of KRASG12C and p38 inhibition on pro-survival transcription factors YAP, TEAD, and CTNNB1. These findings suggest that stress MAPKs are activated by multiple parallel pathways to sustain colorectal cancer viability following KRAS inhibition and may nominate a new class of combination targets with direct KRAS inhibition. Citation Format: Kasturi B. Nayak, Peixin Chen, Yeonjoo Hwang, Bryan C. Pascual, LeeAnn Wang, Jean-philippe Coppe, Chloe E. Atreya, Danielle L. Swaney, Nevan J. Krogan, Julia Carnevale, John D. Gordan. Multi-Omic mapping reveals stress-MAPK dependent mechanisms of resistance to KRASG12C inhibitors in colorectal cancer 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 (5Suppl₁): Abstract nr B043.