KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors
Abstract 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 throug...
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2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06089-y |
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| author | Linyan Tian Chengming Liu Sufei Zheng Huiyang Shi Fang Wei Wenxin Jiang Yucheng Dong Haiyan Xu Enzhi Yin Nan Sun Jie He Yan Wang |
| author_facet | Linyan Tian Chengming Liu Sufei Zheng Huiyang Shi Fang Wei Wenxin Jiang Yucheng Dong Haiyan Xu Enzhi Yin Nan Sun Jie He Yan Wang |
| author_sort | Linyan Tian |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-fe028a2af925407bbba7c8c991670f58 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-fe028a2af925407bbba7c8c991670f582025-01-19T12:37:26ZengBMCJournal of Translational Medicine1479-58762025-01-0123111510.1186/s12967-025-06089-yKEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitorsLinyan Tian0Chengming Liu1Sufei Zheng2Huiyang Shi3Fang Wei4Wenxin Jiang5Yucheng Dong6Haiyan Xu7Enzhi Yin8Nan Sun9Jie He10Yan Wang11Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAbstract 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.https://doi.org/10.1186/s12967-025-06089-yKRAS-G12C inhibitorsKEAP1 mutationsBiomarkersDrug resistanceTargeted therapy |
| spellingShingle | Linyan Tian Chengming Liu Sufei Zheng Huiyang Shi Fang Wei Wenxin Jiang Yucheng Dong Haiyan Xu Enzhi Yin Nan Sun Jie He Yan Wang KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors Journal of Translational Medicine KRAS-G12C inhibitors KEAP1 mutations Biomarkers Drug resistance Targeted therapy |
| title | KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors |
| title_full | KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors |
| title_fullStr | KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors |
| title_full_unstemmed | KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors |
| title_short | KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors |
| title_sort | keap1 mutations as key crucial prognostic biomarkers for resistance to kras g12c inhibitors |
| topic | KRAS-G12C inhibitors KEAP1 mutations Biomarkers Drug resistance Targeted therapy |
| url | https://doi.org/10.1186/s12967-025-06089-y |
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