Pan-cancer analysis of oncogenic MET fusions reveals distinct pathogenomic subsets with differential sensitivity to MET-targeted therapy.

in Cancer discovery by Christopher A Febres-Aldana, Morana Vojnic, Igor Odintsov, Tom Zhang, Ryan Cheng, Catherine Z Beach, Daniel Lu, Marissa S Mattar, Andrea M Gazzo, Leo Gili, Manju Harshan, Ali Ameri, Stephen Machnicki, Xiuying Xiao, William W Lockwood, Xiao-Yan Zhou, Qianlan Yao, Alexander Drilon, Natasha Rekhtman, Nameeta Shah, Anqi Li, Zebing Liu, Soo-Ryum Yang, Monika A Davare, Marc Ladanyi, Romel Somwar

TLDR

  • The study identified two distinct groups of MET-Fs, characterized by different pathobiologies and responses to MET-TKI, and provided a framework to understand their diversity
  • Group 1 MET-Fs are sensitive to MET-TKI, while Group 2 MET-Fs are less responsive
  • Future research should focus on understanding the molecular features of each group and developing targeted therapies

Abstract

MET fusions (MET-Fs) 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-seq plus 11,255 RNA-seq) uncovered two forms of MET-F pathobiology. The first group featured 5' partners with homodimerization domains fused in-frame with MET-tyrosine kinase domain (TKD), 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 pre-clinical models and patients with lung cancer. The second group lacked partner homodimerization motifs and retained MET transmembrane 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 RTK 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.

Overview

  • The study analyzed 56 MET-F-positive tumors from an institutional cohort of 91,119 patients to understand the diverse pathobiology of MET-Fs
  • Two groups of MET-Fs were identified: one with homodimerization domains and another without, which showed distinct pathogenesis and responses to MET tyrosine kinase inhibitors
  • The study aimed to develop a framework to comprehend the heterogeneous landscape of MET-Fs and their oncogenic potential

Comparative Analysis & Findings

  • Group 1 MET-Fs, with homodimerization domains, were primarily translocation-derived, excluded MET exon 14, and showed cytoplasmic aggregation and constitutive activation
  • Group 1 MET-Fs were sensitive to MET tyrosine kinase inhibitors (TKI) in pre-clinical models and patients with lung cancer
  • Group 2 MET-Fs, lacking homodimerization motifs, were characterized by intrachromosomal rearrangements, promoter hijacking, and fusion allele amplification, enriched in gliomas with RTK co-alterations

Implications and Future Directions

  • The study's findings highlight the importance of structural topology and pathogenomic context in determining MET-F oncogenicity and responsiveness to MET-TKI
  • Future studies should investigate the specific molecular features of each MET-F group and explore potential therapeutic strategies for their treatment
  • The development of MET-F-specific biomarkers could aid in disease diagnosis and monitoring
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