Lin Hang, Qu Lingzhi, Wei Hudie, Guo Ming, Chen Xiaojuan, Lin Qianmeng, Zhang Huajun, Dai Shuyan, Chen Yongheng
Department 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.
Department of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha, China.
Commun Biol. 2025 Jan 28;8(1):134. doi: 10.1038/s42003-025-07490-5.
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.
由MET改变引起的c-Met信号通路过度活跃是胃癌的常见机制，也是治疗MET改变的胃癌的一个有吸引力的靶点。然而，目前尚无专门批准用于治疗c-Met扩增型胃癌的c-Met激酶抑制剂。最近，高度选择性的c-Met激酶抑制剂博兹替尼在选择性抑制MET改变的非小细胞肺癌和继发性胶质母细胞瘤方面显示出显著疗效。在本研究中，我们研究了博兹替尼对MET扩增型胃癌的抗肿瘤活性，并阐明其分子机制。博兹替尼通过阻断c-Met信号通路对MET扩增型胃癌细胞产生强大作用，导致细胞增殖和存活受到抑制，以及诱导G0/G1期阻滞和细胞凋亡。在结构上，博兹替尼最佳地嵌入c-Met的ATP口袋中，并通过广泛的相互作用网络牢固结合。此外，博兹替尼有效抑制赋予c-Met耐药性的突变G1163R和Y1230H，尽管其对D1228N和Y1230C突变的效力显著降低。总体而言，我们的研究揭示了博兹替尼针对c-Met的分子机制，突出了其克服获得性耐药突变的能力，并为选择性c-Met抑制剂的进一步设计和改进提供了有价值的见解。
