Safety and Tolerability of c-MET Inhibitors in Cancer

Abstract

The role of aberrant hepatocyte growth factor receptor (c-MET, also known as tyrosine-protein kinase MET)/hepatocyte growth factor (HGF) signaling in cancer progression and invasion has been extensively studied. c-MET inhibitors have shown promising pre-clinical and early phase clinical trial anti-tumor activity in several tumor types, although results of most phase III trials with these agents have been negative. To date, two small molecule c-MET inhibitors, cabozantinib and crizotinib, have been approved by regulatory authorities for the treatment of selected cancer types, but several novel c-MET inhibitors (either monoclonal antibodies or small molecule c-MET tyrosine kinase inhibitors) and treatment combinations are currently under study in different settings. Here we provide an overview of the mechanism of action and rationale of c-MET inhibition in cancer, the efficacy of approved agents, and novel promising c-MET-inhibitors and novel targeted combination strategies under development in different cancer types, with a focus on the safety profile and tolerability of these compounds.

Fig. 1

Main signaling pathways activated through the hepatocyte growth factor (HGF)/hepatocyte growth factor receptor (c-MET) axis and representative HGF/c-MET signaling inhibition strategies. Binding of HGF results in c-MET dimerization and phosphorylation of the tyrosine residues in the intracellular kinase domain. This autophosphorylation leads to the recruitment of signaling effectors like growth factor receptor-bound protein 2 (GRB2) and Grb2-associated adaptor protein 1 (GAB1), which in turn activate downstream signaling pathways such as signal transducer and activator of transcription (STAT), son of sevenless (SOS), proto-oncogene tyrosine-protein kinase SRC (c-SRC), phosphatidylinositol 3-kinase (PI3K), SRC homology domain c-terminal adaptor homolog (SHC), SRC homology protein tyrosine phosphatase 2 (SHP2), and phospholipase Cγ (PLCγ). Further activation of signaling cascades occurs through phosphorylation of SOS/rat sarcoma oncogene homolog (Ras)/RAF proto-oncogene serine/threonine-protein kinase (Raf)/mitogen-activated protein kinases MEK and MAPK, SOS/Ras/Ras-related C3 botulinum toxin substrate (Rac)/GTP-binding protein RHO (Rho)/p21-activated kinase (PAK), SOS/focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K)/FAK, and PI3K/protein kinase B alpha (Akt)/mammalian target of rapamycin (mTOR)/nuclear factor-κB (NF-κB), among others. The activation of these signaling pathways leads to increased cell survival and proliferation, cell motility and invasion, and epithelial-to-mesenchymal transition (EMT). The different therapeutic approaches developed to target the HGF/c-MET axis have been represented. HGF/c-MET inhibition has been approached through two mechanisms of action: monoclonal antibodies (mAbs), anti-HGF and anti-c-MET, and small-molecule inhibitors of the c-MET activity, further divided into adenosine triphosphate (ATP)-competitive inhibitors (selective class I and non-selective class II for c-MET) and non-ATP allosteric competitors (class III)