Anlotinib enhances the efficacy of KRAS-G12C inhibitors through c-Myc/ORC2 axis inhibition in non-small cell lung cancer
Abstract Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality globally, with KRAS mutations present in approximately 20–25% of cases. The KRAS-G12C mutation, occurring in approximately 14% of lung adenocarcinomas, has emerged as a critical target for precision medic...
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| Format: | Article |
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Nature Publishing Group
2025-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07687-w |
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| author | Hongyu Liu Chao Zhou Jun Lu Yuqing Liu Peichen Zou Liang Zhu Huimin Lei Baohui Han |
| author_facet | Hongyu Liu Chao Zhou Jun Lu Yuqing Liu Peichen Zou Liang Zhu Huimin Lei Baohui Han |
| author_sort | Hongyu Liu |
| collection | DOAJ |
| description | Abstract Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality globally, with KRAS mutations present in approximately 20–25% of cases. The KRAS-G12C mutation, occurring in approximately 14% of lung adenocarcinomas, has emerged as a critical target for precision medicine strategies. While KRAS-G12C inhibitors, including sotorasib and adagrasib, have shown promise in clinical trials, their efficacy is limited by primary and acquired resistance mechanisms. This study explored the potential of combining anlotinib, a multi-target tyrosine kinase inhibitor, with KRAS-G12C inhibitors to overcome these resistance challenges in NSCLC treatment. Our results demonstrated that anlotinib improved the sensitivity to KRAS-G12C inhibitors in primary and acquired resistance settings, both in vitro and in vivo. Mechanistically, the combination therapy inhibited c-Myc/ORC2 signaling, leading to cell cycle arrest and apoptosis. These findings suggest that the combination of anlotinib and KRAS-G12C inhibitors represents a promising novel therapeutic approach for KRAS-G12C-mutant NSCLC. |
| format | Article |
| id | doaj-art-577d17a798774fe7bbd17a5b27c215bf |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-577d17a798774fe7bbd17a5b27c215bf2025-08-20T01:47:30ZengNature Publishing GroupCell Death and Disease2041-48892025-05-0116111110.1038/s41419-025-07687-wAnlotinib enhances the efficacy of KRAS-G12C inhibitors through c-Myc/ORC2 axis inhibition in non-small cell lung cancerHongyu Liu0Chao Zhou1Jun Lu2Yuqing Liu3Peichen Zou4Liang Zhu5Huimin Lei6Baohui Han7Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Pharmacology and Chemical Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of MedicineDepartment of Pharmacology and Chemical Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of MedicineDepartment of Pharmacology and Chemical Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of MedicineDepartment of Pharmacology and Chemical Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of MedicineDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineAbstract Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality globally, with KRAS mutations present in approximately 20–25% of cases. The KRAS-G12C mutation, occurring in approximately 14% of lung adenocarcinomas, has emerged as a critical target for precision medicine strategies. While KRAS-G12C inhibitors, including sotorasib and adagrasib, have shown promise in clinical trials, their efficacy is limited by primary and acquired resistance mechanisms. This study explored the potential of combining anlotinib, a multi-target tyrosine kinase inhibitor, with KRAS-G12C inhibitors to overcome these resistance challenges in NSCLC treatment. Our results demonstrated that anlotinib improved the sensitivity to KRAS-G12C inhibitors in primary and acquired resistance settings, both in vitro and in vivo. Mechanistically, the combination therapy inhibited c-Myc/ORC2 signaling, leading to cell cycle arrest and apoptosis. These findings suggest that the combination of anlotinib and KRAS-G12C inhibitors represents a promising novel therapeutic approach for KRAS-G12C-mutant NSCLC.https://doi.org/10.1038/s41419-025-07687-w |
| spellingShingle | Hongyu Liu Chao Zhou Jun Lu Yuqing Liu Peichen Zou Liang Zhu Huimin Lei Baohui Han Anlotinib enhances the efficacy of KRAS-G12C inhibitors through c-Myc/ORC2 axis inhibition in non-small cell lung cancer Cell Death and Disease |
| title | Anlotinib enhances the efficacy of KRAS-G12C inhibitors through c-Myc/ORC2 axis inhibition in non-small cell lung cancer |
| title_full | Anlotinib enhances the efficacy of KRAS-G12C inhibitors through c-Myc/ORC2 axis inhibition in non-small cell lung cancer |
| title_fullStr | Anlotinib enhances the efficacy of KRAS-G12C inhibitors through c-Myc/ORC2 axis inhibition in non-small cell lung cancer |
| title_full_unstemmed | Anlotinib enhances the efficacy of KRAS-G12C inhibitors through c-Myc/ORC2 axis inhibition in non-small cell lung cancer |
| title_short | Anlotinib enhances the efficacy of KRAS-G12C inhibitors through c-Myc/ORC2 axis inhibition in non-small cell lung cancer |
| title_sort | anlotinib enhances the efficacy of kras g12c inhibitors through c myc orc2 axis inhibition in non small cell lung cancer |
| url | https://doi.org/10.1038/s41419-025-07687-w |
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