Abstract 7196: Synergistic effect of sotorasib plus trametinib in patients with KRASG12C-mutated metastatic colorectal cancer

Abstract Background: KRAS is altered in approximately 40% of colorectal cancer (CRC), with the KRASG12C mutant (MUT) being particularly notable for its high prevalence in certain cancers that directly activates the MAPK pathway. Sotorasib, an irreversible, selective KRASG12C inhibitor, showed promising antitumor activity in KRASG12C-MUT colorectal cancer. However, despite recent FDA approval, the response rate of Sotorasib monotherapy in CRC remains below 10%. Herein, we aimed to investigate the synergistic efficacy for the combination of a MEK1 inhibitor (Trametinib) and Sotorasib in CRC. Methods: We conducted an integrative analysis of genomic and transcriptomic data, comparing pretreatment cases and those obtained following the development of resistance to Sotorasib. Dose-response curves were generated to determine the IC50 values of Sotorasib and Trametinib in CRC cell lines with distinct mutational profiles: SW837 (KRASG12C) and SW1463 (KRASG12C and MEK1 MUT). To further investigate the effects of the combination compared to the monotherapy of each drug, we performed a series of functional assays by focusing on perturbations within the MAPK/ERK/AKT signaling pathway. Results: Among the 27 patients analyzed, 10 were identified with putative resistance phenotype, of which 9 (37%) had acquired MEK1 mutations or amplifications. The Kaplan-Meier analysis for overall survival in CRC patients harboring wild-type and mutant MEK1. Functional analysis demonstrated a synergic effect of combined Sotorasib and Trametinib treatment in SW837 and SW1463 CRC cell lines. In MTT assays, the combination therapy significantly enhanced cytotoxicity compared to either monotherapy alone. Similarly, colony formation assay revealed a marked reduction in the proliferative capacity of CRC cells when treated with the combination therapy. Mechanistically, combination treatment with Sotorasib and Trametinib led to enhanced inhibition of the MAPK/ERK/AKT signaling pathway compared to monotherapy in SW837 and SW1463 cell lines. Furthermore, the introduction of activating mutations in MEK1 (MEK1K57T and MEK1K57N) demonstrated that combinatorial therapies of KRASG12C inhibitor and MEK1 inhibitors could effectively overcome the drug resistance acquired by these activating mutations. Conclusion: The combined treatment of Sotorasib and a MEK1 inhibitor, Trametinib, exhibit synergistic effects in drug-induced cytotoxicity and inhibition of MAPK pathways in colorectal cancer lines. Citation Format: Silei Sui, Marwan Fakih, Yuan Li, Caiming Xu, Ajay Goel. Synergistic effect of sotorasib plus trametinib in patients with KRASG12C-mutated metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7196.