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

Huimin Hu, Quanhua Mu, Zhaoshi Bao, Yiyun Chen, Yanwei Liu, Jing Chen, Kuanyu Wang, Zheng Wang, Yoonhee Nam, Biaobin Jiang, Jason K. Sa, Hee Jin Cho, Nam Gu Her, Chuanbao Zhang, Zheng Zhao, Ying Zhang, Fan Zeng, Fan Wu, Xun Kang, Yuqing LiuZenghui Qian, Zhiliang Wang, Ruoyu Huang, Qiangwei Wang, Wei Zhang, Xiaoguang Qiu, Wenbin Li, Do Hyun Nam, Xiaolong Fan, Jiguang Wang, Tao Jiang

Research output: Contribution to journalArticlepeer-review

91 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1665-1678.e18
JournalCell
Volume175
Issue number6
DOIs
Publication statusPublished - 2018 Nov 29
Externally publishedYes

Keywords

  • MET tyrosine-kinase inhibitor
  • PLB-1001
  • cancer genomics
  • clinical trial
  • data science
  • precision neuro-oncology
  • secondary glioblastomas

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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