Research Unit Oncology, the healthcare business of Merck KGaA, Darmstadt, Germany.
Corporate Animal Using Vendor and Vivarium Governance (SQ-AV), Corporate Sustainability, Quality, Trade Compliance (SQ), Animal Affairs (SQ-A), the healthcare business of Merck KGaA, Darmstadt, Germany.
Mol Cancer Ther. 2023 Jul 5;22(7):833-843. doi: 10.1158/1535-7163.MCT-22-0537.
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 antitumor 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 (TKI), 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 MET exon 14 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.
间质-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 突变、基因扩增、重排和过表达。因此，MET 是一个治疗靶点，选择性的 1b 型 MET 抑制剂 tepotinib 被设计用来强力抑制 MET 激酶活性。体外，tepotinib 以浓度依赖性方式抑制 MET，而与 MET 激活方式无关，在体内，tepotinib 在多种癌症适应症的 MET 依赖性肿瘤模型中表现出显著的、剂量依赖性的抗肿瘤活性。Tepotinib 可穿透血脑屏障，并在皮下和原位脑转移模型中显示出强大的抗肿瘤活性，与患者观察到的临床活性一致。MET 扩增是对表皮生长因子受体酪氨酸激酶抑制剂（TKI）耐药的既定机制，临床前研究表明 tepotinib 与 EGFR TKIs 联合使用可以克服这种耐药性。Tepotinib 目前被批准用于治疗携带 MET 外显子 14 跳跃改变的晚期或转移性非小细胞肺癌成人患者。本文综述了 tepotinib 在携带 MET 改变的临床前癌症模型中的药理学特性，并证明了严格遵循药理学审核线索原则可能会导致精准医学的成功发现和开发。
