Abstract Colorectal cancer (CRC) is a highly ERK driven tumor. ERK pathway activation in CRC most commonly results from activating mutations in RAS or BRAF, occurring in over half of cases, or from ligand dysregulation activating the epidermal growth factor receptor (EGFR). Despite the importance of ERK signaling, ERK pathway inhibitors have been less effective for CRC compared to other cancer types, with their activity limited by rapid adaptive and acquired resistance. High basal receptor tyrosine kinase (RTK) signaling, predominantly from EGFR, in the bowel is reactivated with RAS/BRAF oncogene inhibition, leading to incomplete ERK pathway suppression with RAS/BRAF inhibitor monotherapy and attenuation of treatment response. Combination therapy is thus needed to sufficiently inhibit ERK and achieve clinical responses. We and others have shown that adding EGFR inhibitors to selective RAS inhibitors improves treatment response. For example, combined KRAS G12C and EGFR inhibitors are currently FDA-approved for the treatment of KRAS G12C mutant CRC. However, these targeted therapy combinations remain limited by relatively short-lived responses. Analysis of paired pre-treatment and progression samples from patients with CRC treated with targeted therapy suggests that tumors with baseline high chromosomal instability develop resistance more quickly, with amplification a recurrent and early mechanism of resistance. Novel therapeutic combinations, given together with RAS and EGFR inhibitors, that can prevent the emergence of amplifications are proposed to extend the duration of response. Citation Format: Rona Yaeger. Combination strategies to overcome adaptive and acquired resistance to RAS targeted therapy 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 IA014.
Rona Yaeger (2026) studied this question.