生物
融合基因
酪氨酸激酶
跨膜蛋白
癌变
背景(考古学)
癌症研究
跨膜结构域
外显子
癌症
受体酪氨酸激酶
蛋白激酶结构域
遗传学
基因
激酶
信号转导
受体
突变体
古生物学
作者
Christopher A. Febres‐Aldana,Morana Vojnic,Igor Odintsov,Tom Zhang,Ryan Cheng,Catherine Z. Beach,Daniel Lu,Marissa S. Mattar,Andrea Gazzo,Leo Gili,Manju Harshan,Afshin Ameri,Stephen Machnicki,Xiuying Xiao,William W. Lockwood,Xiaoyan Zhou,Qianlan Yao,Alexander Drilon,Natasha Rekhtman,Nameeta Shah
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2025-02-18
卷期号:15 (6): 1141-1158
被引量:8
标识
DOI:10.1158/2159-8290.cd-24-0417
摘要
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.
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