Targeting c-MET: An Effective Anti-Cancer Therapeutic Strategy?
Joanna Evans, Claire Seedhouse, and Tracey D Bradshaw*
ABSTRACT
The mesenchymal-epithelial transition factor (MET) proto-oncogene encodes the receptor tyrosine kinase c-MET, a critical regulator of cellular proliferation, survival, and motility. Aberrant c-MET activation, most commonly through gene amplification and exon 14 skipping mutations, drives oncogenesis across multiple malignancies and promotes tumour progression and therapeutic resistance. The oncogenic roles of c-MET have established it as an important pharmacological target. This review aims to critically evaluate c-MET-targeted pharmacological strategies, including tyrosine kinase inhibitors (capmatinib, tepotinib and cabozantinib) and antibody-based approaches (rilotumumab and onartuzumab). Small-molecule inhibitors have demonstrated clinical efficacy, particularly in c-MET exon 14 skipping-positive non-small-cell lung cancer, whilst antibody approaches have shown limited clinical benefit, reflecting ligand-independent activation and pathway redundancy. Resistance mechanisms, including secondary kinase domain mutations, bypass signalling, and downstream pathway reactivation, further limit a durable response. Emerging strategies, including biomarker-guided trial design and antibody-drug conjugates, aim to overcome these challenges by aligning therapy with tumour-specific c-MET dependency and optimising drug design for target selectivity. Collectively, the evidence suggests that for durable benefit from c-MET-targeted therapies, there is a need for accurate identification of c-MET-dependent tumours coupled with molecular optimisation of drug design for improved specificity.
