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Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer
Hang Lin1, Lingzhi Qu1, Hudie Wei1
1Department 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 University, Changsha, China.
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.
Insights
Bozitinib effectively targets MET-amplified gastric cancer by inhibiting the c-Met pathway, halting cancer cell growth and survival. This study reveals its mechanism and potential to overcome resistance mutations.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hyperactive c-Met signaling due to MET alterations is a key driver in gastric cancer.
- Targeting the c-Met pathway is a promising strategy, but no specific inhibitors exist for c-Met-amplified gastric cancer.
- Bozitinib, a selective c-Met inhibitor, has shown efficacy in other cancers.
Purpose of the Study:
- To investigate the antitumor activity of bozitinib in MET-amplified gastric cancer.
- To elucidate the molecular mechanisms underlying bozitinib's action.
- To assess bozitinib's efficacy against resistance-conferring MET mutations.
Main Methods:
- In vitro testing of bozitinib on MET-amplified gastric cancer cells.
- Analysis of cell proliferation, survival, cell cycle, and apoptosis.
- Structural analysis of bozitinib binding to c-Met.
- Evaluation of bozitinib's activity against specific MET resistance mutations.
Main Results:
- Bozitinib strongly inhibited proliferation and survival of MET-amplified gastric cancer cells.
- Bozitinib induced G0/G1 phase arrest and apoptosis.
- Structural analysis showed optimal binding of bozitinib in the c-Met ATP pocket.
- Bozitinib inhibited G1163R and Y1230H mutations but showed reduced potency against D1228N and Y1230C mutations.
Conclusions:
- Bozitinib demonstrates significant antitumor activity against MET-amplified gastric cancer.
- The drug functions by blocking the c-Met signaling pathway, inducing cell cycle arrest and apoptosis.
- Bozitinib shows potential in overcoming certain acquired resistance mutations, offering insights for future inhibitor design.
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