Novel resistance mutations and “hotspots” identified for MET inhibitor types.
(A) Collapsed heatmap of common resistance positions along the kinase domain, with the wild-type protein sequence and secondary structure annotated. Each tile represents a sum of counts for statistically filtered resistance mutations across all inhibitors for type I (pink), type II (blue), and the type I½ inhibitor AMG-458 (green), with the scale bar reflecting counts of resistance mutations across respective inhibitor types. (B-D) Expanded heatmap showing each resistance position and the counts for each specific resistance mutation across all inhibitor types type I (pink), type II (blue), and the type I½ inhibitor AMG-458 (green). Wild-type sequence and variant change are annotated. (E-F) Average frequency of resistance mutations for each mapped on to a representative type I (crizotinib, 2WGJ) and type II (merestinib, 4EEV) crystal structure, alongside the type I½, AMG-458 structure (5T3Q), with associated scale bars. Individual positions with high resistance mutation frequencies are annotated on each structure, with a zoom-in of the bound inhibitor and surrounding resistance sites. (G) Venn diagram showing mutations shared among type I (pink), type II (light blue), and type I½ (green). (H) Structurally mapped (PDB 2WGJ) resistance positions shared among type I, II, I½ (blue-gray), type I and II (purple), type I and I½ (dusty rose), type II and I½ (teal) inhibitors.