SynthesisJournal of translational medicine2025
KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors.
Synthesis in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Advances in targeting KRAS mutations: A promising approach for the treatment of non‑small cell lung cancer (Review).Oncology reports · 2026Review
- KRAS Inhibition in Pancreatic Ductal Adenocarcinoma.Journal of clinical medicine · 2026Review
- Astatine-211-Labeled Therapy Targeting Amino Acid Transporters: Overcoming Drug Resistance in Non-Small Cell Lung Cancer.International journal of molecular sciences · 2025Review
- Advances in biomarkers of resistance to KRAS mutation-targeted inhibitors.Discover oncology · 2025Review
- KRAS G12C Inhibition in Solid Tumors: Biological Breakthroughs, Clinical Evidence, and Open Challenges.Cancers · 2025Review
- Review
- The supramolecular polymer-related signature predicts prognosis and indicates immune microenvironment infiltration in gastric cancer.Clinics (Sao Paulo, Brazil) · 2025Article
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Authors and funding
12 authors.
Funding
Abstract
backgroundKRAS-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.
methodsThis 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.
resultsAnalysis 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.
conclusionThis 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.
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