MET Fusions May Be Druggable Targets in Pediatric Glioblastoma

Despite the identification of commonly deregulated signaling pathways and recurrent mutations in histone and chromatin modifier genes in pediatric glioblastoma, no molecularly targeted therapies are available. To identify additional potentially targetable recurrent alterations, Bender and colleagues performed whole-genome sequencing of tumor and blood DNA from 53 patients with pediatric glioblastoma and 5 pediatric glioblastoma cell lines. Mutations or deletions in genes involved in cell-cycle regulation occurred in the majority of samples, and alterations affecting receptor tyrosine kinase–PI3K–MAPK signaling were also frequently observed. Additionally, RNA sequencing of 42 tumors revealed rearrangements resulting in fusion transcripts in 64% of tumors. MET, which encodes an oncogenic tyrosine kinase, was most commonly affected in approximately 10% of tumors; two fusions, TFG­–MET and CLIP2–MET, that retain only the C-terminus of MET were identified, as well as PTPRZ1–MET fusions that express full-length MET under the control of the active PTPRZ1 promoter. Overexpression of TFG–MET or PTPRZ1–MET resulted in increased phosphorylation of MET and ERK, indicating activation of downstream MAPK signaling, and treating human astrocyte cells overexpressing TFG–MET with a MET inhibitor abolished TFG–MET-induced MAPK activation. Similarly, in vivo, TFG–MET expression in nestin-positive cells induced glioma-like tumors in Cdkn2a^−/− or Trp53^−/− mice, whereas MET inhibitor treatment slowed tumor growth and extended survival. Further, MET inhibition reduced the growth of intracranially transplanted CLIP2–MET expressing tumor cells, and reduced ERK phosphorylation. Based on these findings, an 8-year-old patient with recurrent PTPRZ1–MET-positive glioblastoma was treated with the FDA-approved MET kinase inhibitor crizotinib. Crizotinib induced tumor shrinkage, but drug-resistant lesions emerged that resulted in rapid progression and death. The identification of MET fusions in pediatric glioblastoma suggests the potential for targeting MET in a subset of patients. However, combination treatments will likely be required to overcome resistance, and further investigation is needed to uncover the underlying resistance mechanism.

International Cancer Genome Consortium PedBrain Tumor Project. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma. Nat Med 2016 Oct 17 [Epub ahead of print].