KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors

Background: KRAS-G12C inhibitors mark a notable advancement in targeted cancer therapies, yet identifying predictive biomarkers for treatment efficacy and resistance remains essential for optimizing clinical outcomes.

Methods: This systematic meta-analysis synthesized studies available through September 2024 across PubMed, Cochrane Library, SpringerLink, and Embase. Using CRISPR/Cas9 technology, this study generated cells with KEAP1 and STK11 knockouts, and utilized lentiviral vectors to overexpress PD-L1. Cellular sensitivity to KRAS-G12C inhibitors-AMG510, MRTX849, and JAB-21822-was evaluated through CCK-8 assays. Comprehensive bioinformatics analyses on stably transfected cell lines were conducted to elucidate pathways mediating resistance.

Results: Analysis of 13 studies involving 1132 patients highlighted the significant efficacy of KRAS-G12C inhibitor monotherapy, particularly among elderly and female patients. Treatment response was notably affected by liver and brain metastases, with KEAP1 mutations identified as a primary negative prognostic factor, closely associated with early resistance to treatment. Validation studies in NCI-H358 cells showed a marked increase in IC50 values for AMG510, MRTX849, and JAB-21822 after KEAP1 knockout (P < 0.0001), with IC50 values rising from 27.78 nm, 116.9 nm, and 118.7 nm in controls, respectively. Comparative analysis of differentially expressed genes in KEAP1 knockout cells versus controls, utilizing GO, KEGG, and Reactome pathway analyses, revealed substantial enrichment in pathways linked to extracellular matrix organization and cell adhesion processes. Although STK11 mutations and heightened PD-L1 expression indicated a trend toward poorer outcomes, these correlations lacked statistical significance.

Conclusion: This research affirms KRAS-G12C inhibitors as promising treatments, especially for certain patient subgroups, and underscores KEAP1 mutations as key biomarkers for resistance. The findings highlight the urgent need for alternative therapeutic approaches in KEAP1-mutant patients and emphasize the role of molecular profiling in tailored treatment strategies.