Pan-Cancer Analysis of Oncogenic MET Fusions Reveals Distinct Pathogenomic Subsets with Differential Sensitivity to MET-Targeted Therapy.

ABSTRACT: MET fusions (MET-F) are oncogenic drivers that remain poorly characterized. Analysis of 56 MET-F-positive tumors from an institutional cohort of 91,119 patients (79,864 DNA sequencing plus 11,255 RNA sequencing) uncovered two forms of MET-F pathobiology. The first group featured 5' partners with homodimerization domains fused in-frame with the MET tyrosine kinase domain, primarily originated from translocations, frequently excluded MET exon 14, mediated oncogenesis through cytoplasmic aggregation and constitutive activation, and were markedly sensitive to MET tyrosine kinase inhibitors (TKI) in preclinical models and patients with lung cancer. The second group lacked partner homodimerization motifs and retained MET transmembrane and extracellular domains. Their pathogenesis involved intrac

SUBMITTER: Febres-Aldana CA 

PROVIDER: S-EPMC12133426 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature