<p>MET TKD mutations in NSCLC cohort of Caris Life Sciences. (A) Flowchart of the NSCLC subgroup in the Caris Life Sciences dataset. (B) Prevalence of MET TKD mutations in NSCLC cases in the Caris Life Sciences dataset (MET TKD mutations in 280 unique patients). (C) Lollipop plot of the oncogenic / likely oncogenic MET TKD mutations detected in NSCLC cases in the Caris Life Sciences dataset (35 oncogenic / likely oncogenic MET TKD mutations in 35 unique patients). (D) concurrent driver alterations (information available for 24 cases, unavailable for 11 cases) and (E) concurrent MET amplification status (information available for 33 cases, unavailable for 2 cases) of NSCLC cases harboring oncogenic / likely oncogenic MET TKD mutations in the Caris Life Sciences dataset.</p>
<p>Western blot analysis of MET and ERK1/2 phosphorylation in MET R1170Q cell models. MET and ERK1/2 phosphorylation in (A) Ba/F3 cells stably transduced with MET R1170Q and (B) 293T cells transiently overexpressing MET R1170Q. Cells were treated with MET TKIs at the indicated dose for Ba/F3 cells or at 1 μM for 293T cells.</p>
<div>Abstract<p>Activating point mutations in the <i>MET</i> tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating <i>MET</i> TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the <i>MET</i> TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring <i>MET</i> TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating <i>MET</i> TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors.</p><p><b>Significance:</b> The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic <i>MET</i> tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.</p></div>
<p>Equilibration of interactions that drives ATP affinity in the presence MET F1200I mutant. (A) Representative structure of ATP bound MET F1200I with the regions of interest highlighted [alpha C helix (red), DFG site (green), mutation site (blue)]. (B) π - π stacking interactions that bridge the alpha C helix and DFG site are conformationally controlled through residues position 1200. π - π stacking interactions were calculated between ring centers. Distances between F1200I and neighboring residues were measured from the F1200I side chain center of mass to the ring centers of the aromatic rings. (C) root-mean-square-fluctuation (RMSF) calculations show a stabilization of the activation loop in the F1200I system.</p>
