BACKGROUND: Mutations in c-MET receptor tyrosine kinase (MET) can be primary oncogenic drivers of multiple tumour types or can be acquired as mechanisms of resistance to therapy. MET tyrosine kinase inhibitors (TKIs) are classified as type I or type II inhibitors, with the former binding to the DFG-in, active conformation of MET, and the latter to the DFG-out, inactive conformation of MET. Understanding how the different classes of MET TKIs impact tumours with varied MET alterations is critical to optimising treatment for patients with MET altered cancers. Here, we characterise MET mutations identified in patients' tumours and assess responsiveness to type I and II TKIs. METHODS: We used structural modelling, in vitro kinase and in cell-based assays to assess the response of MET mutations to type I and II TKIs. We then translated our pre-clinical findings and treated patients with MET mutant tumours with selected inhibitors. RESULTS: We detected the emergence of four (three previously uncharacterised and one known) MET resistance mutations (MET(G1090A), MET(D1213H), MET(R1227K) and a MET(Y1230S)) in samples from patients with multiple solid tumours, including patients who had been previously treated with type I inhibitors. In silico modelling and biochemical assays across a variety of MET alterations, including the uncharacterised MET(G1090A) and the MET(Y1230S) substitutions, demonstrated impaired binding of type I but not of type II TKIs (i.e., cabozantinib/foretinib). Applying our pre-clinical findings, we then treated two patients (one with a non-small-cell lung cancer and one with a renal cell carcinoma) whose tumours harboured these previously uncharacterised MET alterations with cabozantinib, a type II MET TKI, and observed clinical responses. CONCLUSIONS: Comprehensive characterisation of the sensitivity of mutations to different TKI classes in oncogenic kinases may guide clinical intervention and overcome resistance to targeted therapies in selected cases. KEY POINTS: Kinase mutations in RTKs are primary or secondary drivers in multiple cancer types Some of these mutations confer resistance to type I but not to type II inhibitors in preclinical samples and in patients The biochemical characterization of mutations in oncogenic kinases based on their sensitivity to type I and type II inhibitors is crucial to inform clinical intervention.