间充质上皮转化因子（MET）原癌基因编码MET受体酪氨酸激酶。MET异常通过多种分子机制驱动多种癌症类型的肿瘤发生，包括MET基因突变、基因扩增、重排和过表达。因此，MET是一种治疗靶点，选择性Ib型MET抑制剂tepotinib被设计为强力抑制MET激酶活性。体外实验表明，tepotinib以浓度依赖方式抑制 MET的激活，无论MET激活的方式如何，在体内，tepotinib在多种癌症表型的MET依赖性肿瘤模型中表现出显著、剂量依赖性的抗肿瘤活性。tepotinib可以穿过血脑屏障，在皮下和原位脑转移模型中显示出强烈的抗肿瘤活性，与患者的临床活性一致。MET扩增是耐受EGFR酪氨酸激酶抑制剂（TKIs）的已知机制，临床前研究表明，tepotinib与EGFR TKIs联合使用可以克服这种耐受性。tepotinib目前已获批用于治疗携带METex14跳过突变的晚期或转移性非小细胞肺癌成人患者。本综述重点阐述了tepotinib在含有MET变异的临床前癌症模型中的药理学，并证明了严格遵守药理审查路径的原则可能导致精准医疗的成功发现和开发。

The mesenchymal-epithelial transition factor (MET) proto-oncogene encodes the MET receptor tyrosine kinase. MET aberrations drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET mutations, gene amplification, rearrangement, and overexpression. Therefore, MET is a therapeutic target and the selective type Ib MET inhibitor, tepotinib, was designed to potently inhibit MET kinase activity. In vitro, tepotinib inhibits MET in a concentration-dependent manner irrespective of the mode of MET activation, and in vivo, tepotinib exhibits marked, dose-dependent antitumor activity in MET-dependent tumor models of various cancer indications. Tepotinib penetrates the blood-brain barrier and demonstrates strong anti-tumor activity in subcutaneous and orthotopic brain metastasis models, in-line with clinical activity observed in patients. MET amplification is an established mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) and preclinical studies show that tepotinib in combination with EGFR TKIs can overcome this resistance. Tepotinib is currently approved for the treatment of adult patients with advanced or metastatic non-small cell lung cancer harboring METex14 skipping alterations. This review focuses on the pharmacology of tepotinib in preclinical cancer models harboring MET alterations, and demonstrates that strong adherence to the principles of the Pharmacological Audit Trail may result in a successful discovery and development of a precision medicine.