Hepatocyte growth factor receptor and AXL receptor tyrosine kinase (MET/AXL)

Hepatocyte growth factor receptor (MET) and AXL receptor tyrosine kinase (AXL) are critical signaling proteins that regulate cell survival, migration, and the epithelial-to-mesenchymal transition (EMT) [1][2]. MET is activated by its ligand, hepatocyte growth factor (HGF), and its dysregulation via amplification or mutation (such as MET exon 14 skipping) is a primary driver in non-small cell lung cancer and gastric cancers [1][4]. AXL, a member of the TAM (Tyro3, Axl, Mer) family, is frequently overexpressed in response to cellular stress and serves as a major bypass mechanism for resistance to other targeted therapies, such as EGFR or HER2 inhibitors [2][5]. The additional RTKs typically associated with this profile include VEGFR2, RET, KIT, and TIE2, which are involved in tumor neoangiogenesis and the modulation of the tumor microenvironment [3][6]. Multi-kinase inhibitors like cabozantinib and sitravatinib are designed to target this broad spectrum of receptors to simultaneously inhibit tumor growth, block angiogenic pathways, and reverse EMT-mediated drug resistance [3][7]. These drugs function by competitively binding to the intracellular ATP-binding pocket of the kinase domains, preventing the autophosphorylation necessary for downstream signaling through the PI3K/AKT and MAPK/ERK pathways [3][8]. Clinical management of patients on these therapies requires monitoring for class-specific adverse events, including hypertension, palmar-plantar erythrodysesthesia, and potential gastrointestinal perforations [3][9]. Identifying patients through biomarkers such as MET amplification or AXL overexpression is essential for optimizing therapeutic efficacy in advanced solid tumors [4][10].

Other names

HGFRMETAXLUFOTyrosine-protein kinase MetTyrosine-protein kinase AXLTAM family receptorsMET/AXL/VEGFR profile

Small molecule inhibition of the intracellular tyrosine kinase domains of MET, AXL, and other receptor tyrosine kinases (RTKs), which prevents ATP binding and subsequent autophosphorylation, thereby blocking downstream oncogenic signaling pathways such as PI3K/AKT, MAPK/ERK, and STAT3 [3][8].