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

Author Type(s)

Student

Document Type

Article

Publication Date

6-1-2025

DOI

10.1158/2159-8290.CD-24-0417

Journal Title

Cancer Discovery

Disciplines

Medicine and Health Sciences

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 trans-membrane and extracellular domains. Their pathogenesis involved intrachromosomal rearrangements, resulting in partner selection for promoter hijacking and fusion allele amplification. Membrane-bound fusions were enriched in gliomas with receptor tyrosine kinase co-alterations. We provide a framework to comprehend the heterogeneous landscape of MET-Fs, supporting that fusion oncogenicity and MET TKI sensitivity are determined by structural topology and pathogenomic context.

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