Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer
Abstract Hyperactive c-Met signaling pathway caused by altered MET is a common mechanism underlying gastric cancer and represents an attractive target for the treatment of gastric cancer with MET alterations. However, no c-Met kinase inhibitors are currently approved specifically for the treatment o...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07490-5 |
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| author | Hang Lin Lingzhi Qu Hudie Wei Ming Guo Xiaojuan Chen Qianmeng Lin Huajun Zhang Shuyan Dai Yongheng Chen |
| author_facet | Hang Lin Lingzhi Qu Hudie Wei Ming Guo Xiaojuan Chen Qianmeng Lin Huajun Zhang Shuyan Dai Yongheng Chen |
| author_sort | Hang Lin |
| collection | DOAJ |
| description | Abstract Hyperactive c-Met signaling pathway caused by altered MET is a common mechanism underlying gastric cancer and represents an attractive target for the treatment of gastric cancer with MET alterations. However, no c-Met kinase inhibitors are currently approved specifically for the treatment of c-Met-amplified gastric cancer. Recently, bozitinib, a highly selective c-Met kinase inhibitor, has shown remarkable potency in selectively inhibiting MET-altered non-small cell lung cancer and secondary glioblastoma. In this study, we investigate the antitumor activity of bozitinib against MET-amplified gastric cancer and elucidate its molecular mechanism. Bozitinib demonstrates a strong effect on MET-amplified gastric cancer cells by blocking the c-Met signaling pathway, leading to the inhibition of cell proliferation and survival, as well as the induction of G0/G1 phase arrest and apoptosis. Structurally, bozitinib is optimally embedded in the ATP pocket of c-Met and firmly binds via an extensive interaction network. In addition, bozitinib efficiently inhibits c-Met resistance-conferring mutations G1163R and Y1230H, although its potency is significantly decreased against the D1228N and Y1230C mutations. Overall, our study reveals the molecular mechanism of bozitinib against c-Met, highlights its ability to overcome acquired resistance mutations, and provides valuable insights into further design and improvement of selective c-Met inhibitors. |
| format | Article |
| id | doaj-art-5bd08fcc319249929bb63cbedd8924f4 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-5bd08fcc319249929bb63cbedd8924f42025-02-02T12:37:24ZengNature PortfolioCommunications Biology2399-36422025-01-018111110.1038/s42003-025-07490-5Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancerHang Lin0Lingzhi Qu1Hudie Wei2Ming Guo3Xiaojuan Chen4Qianmeng Lin5Huajun Zhang6Shuyan Dai7Yongheng Chen8Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South UniversityDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityAbstract Hyperactive c-Met signaling pathway caused by altered MET is a common mechanism underlying gastric cancer and represents an attractive target for the treatment of gastric cancer with MET alterations. However, no c-Met kinase inhibitors are currently approved specifically for the treatment of c-Met-amplified gastric cancer. Recently, bozitinib, a highly selective c-Met kinase inhibitor, has shown remarkable potency in selectively inhibiting MET-altered non-small cell lung cancer and secondary glioblastoma. In this study, we investigate the antitumor activity of bozitinib against MET-amplified gastric cancer and elucidate its molecular mechanism. Bozitinib demonstrates a strong effect on MET-amplified gastric cancer cells by blocking the c-Met signaling pathway, leading to the inhibition of cell proliferation and survival, as well as the induction of G0/G1 phase arrest and apoptosis. Structurally, bozitinib is optimally embedded in the ATP pocket of c-Met and firmly binds via an extensive interaction network. In addition, bozitinib efficiently inhibits c-Met resistance-conferring mutations G1163R and Y1230H, although its potency is significantly decreased against the D1228N and Y1230C mutations. Overall, our study reveals the molecular mechanism of bozitinib against c-Met, highlights its ability to overcome acquired resistance mutations, and provides valuable insights into further design and improvement of selective c-Met inhibitors.https://doi.org/10.1038/s42003-025-07490-5 |
| spellingShingle | Hang Lin Lingzhi Qu Hudie Wei Ming Guo Xiaojuan Chen Qianmeng Lin Huajun Zhang Shuyan Dai Yongheng Chen Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer Communications Biology |
| title | Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer |
| title_full | Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer |
| title_fullStr | Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer |
| title_full_unstemmed | Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer |
| title_short | Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer |
| title_sort | characterization of bozitinib as a potential therapeutic agent for met amplified gastric cancer |
| url | https://doi.org/10.1038/s42003-025-07490-5 |
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