Abstract 4722: Crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors

Abstract Objective: KRAS-G12C inhibitors are promising in targeted therapeutic strategies. However, it remains uncertain to search for biological reminders of clinical outcomes and early resistance. Methods: Systematic review has been performed up to September, 2024 to evaluate treatment efficacy and beneficial patients. We constructed KEAP1 and STK11 knockout mutants with CRISPR/Cas9 technology and PD-L1 overexpression mutants with lentiviral vectors. The sensitivity of cells to different KRAS-G12C inhibitors was assessed using CCK-8 assays. Potential pathways of resistance were identified through comprehensive bioinformatics analyses. Results: 13 clinical trials with 1, 132 enrolled patients indicated remarkable clinical efficacy and benefit the senior and the female. Patients with liver and brain metastases also tends to benefit from KRAS-G12C inhibitors. KEAP1 mutation serves as a critical negative biomarker for early progression and resistance. Validation studies indicated a notable increase in IC50 values for different KRAS-G12C inhibitors after KEAP1 knockout (P < 0.0001). Differentially expressed genes in KEAP1 knockout cells versus contrast groups were conducted with GO, KEGG, and Reactome pathway analyses, suggested evident enrichment in extracellular matrix organization and cell adhesion processes. In addition, STK11 mutations and an increasing PD-L1 expression level reminds of worse prognosis, despite absence of significant difference. Conclusion: This research considered KRAS-G12C inhibitors as optional therapy and selected some subgroups who are more likely gain benefits from targeted therapy. As a key adverse biomarker, KEAP1 mutation tends to affect extracellular matrix organization and cell adhesion and promotes early resistance. Citation Format: Yan Wang, Linyan Tian, Chengming Liu, Sufei Zheng, Huiyang Shi, Fang Wei, Wenxin Jiang, Yucheng Dong, Haiyan Xu, Enzhi Yin, Nan Sun, Jie He. Crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors [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 4722.