医学
癌症研究
受体酪氨酸激酶
药理学
癌症
肺癌
酪氨酸激酶抑制剂
卡波扎尼布
肿瘤科
内科学
受体
作者
Joachim Albers,Manja Friese‐Hamim,Anderson Clark,Oliver Schadt,Gina Walter-Bausch,Christopher Stroh,Andreas Johne,Niki Karachaliou,Andree Blaukat
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2023-03-30
卷期号:22 (7): 833-843
被引量:3
标识
DOI:10.1158/1535-7163.mct-22-0537
摘要
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.
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