MET fusions and splicing variants convergently define a subgroup of glioma sensitive to MET inhibitors

Purpose: Our previous study has shown that PTPRZ1-MET (ZM) fusion is a viable target for MET inhibitors in gliomas. However, the diversity and prevalence of somatic MET alterations in diffuse gliomas are still elusive and need to be extensively characterized for identifying novel therapeutic targets. Methods: Totally, 1,350 glioma patients and 31 patient-derived cells were collected from the Chinese Glioma Genome Atlas (CGGA) and published data. All kinds of MET fusions and/or splicing variants (MET F/SVs) were identified by bioinformatical methods. Single-cell RNA sequencing (scRNA-seq) were used for validation. In vitro experiments of drug resistance were conducted for the possibility of MET-targeted treatment. Results: MET F/SVs but not genomic amplification, were highly enriched in the secondary glioblastomas (sGBM) and marked worse prognosis. Further molecular and scRNA-seq analysis revealed that MET F/SVs were induced in the course of glioma evolution and highly associated with MET overexpression. Subsequent in vitro and the clinical study showed that cells and patients harboring MET F/SVs have better response to MET inhibitors. Conclusion: Our findings expanded the percentage of gliomas with abnormal MET alterations and suggested that a subgroup of gliomas harboring MET F/SVs may benefit from MET-targeted therapy.