Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor

• Huimin Hu ^[1] ; Quanhua Mu ^[2] ; Zhaoshi Bao ^[1]
  1. [1] Capital Medical University

     Capital Medical University

     China

     
  2. [2] Hong Kong University of Science and Technology

     Hong Kong University of Science and Technology

     RAE de Hong Kong (China)

     
• Localización: Cell, ISSN 0092-8674, Vol. 175, Nº. 6, 2018, págs. 1665-1678
• Idioma: inglés
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• Resumen

  • Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in ∼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.