Pan-cancer analysis of oncogenic MET fusions reveals distinct pathogenomic subsets with differential sensitivity to MET-targeted therapy Journal Article
| Authors: | Febres-Aldana, C. A.; Vojnic, M.; Odintsov, I.; Zhang, T.; Cheng, R.; Beach, C. Z.; Lu, D.; Mattar, M. S.; Gazzo, A. M.; Gili, L.; Harshan, M.; Ameri, A.; Machnicki, S.; Xiao, X.; Lockwood, W. W.; Zhou, X. Y.; Yao, Q.; Drilon, A.; Rekhtman, N.; Shah, N.; Li, A.; Liu, Z.; Yang, S. R.; Davare, M. A.; Ladanyi, M.; Somwar, R. |
| Article Title: | 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 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. SIGNIFICANCE: MET fusions are primary drivers of tumor growth in multiple tumor types - lung cancer and gliomas - and can be effectively targeted with either type I (crizotinib, capmatinib, tepotinib, and savolitinib) or type II (cabozantinib) MET TKIs, with best responses in tumors harboring fusions with partner homodimerization. ©2025 American Association for Cancer Research. |
| Keywords: | genetics; neoplasm; neoplasms; metabolism; protein kinase inhibitor; pathology; protein kinase inhibitors; oncogene proteins, fusion; drug therapy; scatter factor receptor; molecularly targeted therapy; proto-oncogene proteins c-met; molecular targeted therapy; met protein, human; humans; human; oncogene fusion protein |
| Journal Title: | Cancer Discovery |
| Volume: | 15 |
| Issue: | 6 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-06-01 |
| Start Page: | 1141 |
| End Page: | 1158 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-24-0417 |
| PUBMED: | 39965191 |
| PROVIDER: | scopus |
| PMCID: | PMC12133426 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Romel Somwar -- Source: Scopus |
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