非小细胞肺癌MET基因改变及治疗进展

MET alterations and therapeutic strategies in non-small cell lung cancer

MET基因在维持细胞稳态、运动和凋亡中起着至关重要的作用。在肿瘤中,MET基因改变促进肿瘤细胞的增殖、侵袭和转移。在非小细胞肺癌(non-small cell lung cancer, NSCLC)中,MET基因改变包括MET 14号外显子跳跃突变(METex14)、MET扩增(METamp)、MET融合(MET fusion)、MET酪氨酸激酶区域的错义突变(MET-tyrosine kinase domain, MET-TKD)和MET蛋白过度表达。基于对MET基因及信号通路的认识,研究者们提出了三种靶向MET的方法:MET酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI),包括克唑替尼、卡马替尼、特泊替尼、赛沃替尼和卡博替尼;MET或其配体肝细胞生长因子(hepatocyte growth factor, HGF)单克隆抗体,包括依玛妥珠单抗(Emibetuzumab),AV-299(Ficlatuzumab);和MET或HGF抗体偶联药物和双特异性抗体,包括替利妥珠单抗(Telisotuzumab vedotin)和埃万妥单抗(Amivantamab)。本文对MET基因改变及其治疗进展进行述评,以期为MET基因改变的NSCLC患者的精准治疗推荐意见,为解决靶向治疗和免疫治疗的增效和耐药问题提供新思路。

Mesenchymal to epithelial transition factor(MET) often plays a crucial role in cell homeostasis, motility and apoptosis, while its alterations can promote the proliferation, invasion and metastasis of tumors cells. In non-small cell lung cancer(NSCLC), MET genetic alterations include MET exon 14 skipping mutations, MET amplification, MET fusion, MET-tyrosine kinase domain and overexpression. Based on the understanding of the potential therapeutic targets of MET, the investigators propose 3 strategies of MET targeting for clinical trials: MET tyrosine kinase inhibitors(TKIs), including crizotinib, capmatinib, tepotinib, savolitinib, and cabozantinib;MET or hepatocyte growth factor(HGF) monoclonal antibodies, including emibetuzumab vedotin and ficlatuzumab;and MET or HGF antibody-drug conjugate and bispecific antibodies, including telisotuzumab and amivantamab. In this article, we review the progress of MET genetic alteration and its treatment progress, hope to provide more precise treatment for the patients with MET alterations, and provide new ideas for the efficacy and drug resistance of targeted therapy and immunotherapy.