Extensive MET alterations confer clinical response to MET inhibitors in gliomas

Abstract

Activating alterations of the MET gene are well-characterized oncogenic drivers, and MET inhibitors could successfully treat several tumor types with MET alterations, including gliomas with PTPRZ1-MET fusion. However, the full diversity and prevalence of MET alterations in gliomas are still lacking to accurately identify a subset of patients likely to benefit from MET inhibitor treatment. Here, we interrogated genomic profiles of 1,351 gliomas, and further identify 60 cases harboring MET alterations, including MET fusions and various MET exon skipping events. MET RNA alterations, but not MET amplification, are highly enriched in the secondary glioblastomas (sGBM) with significantly worse prognosis. Further molecular analysis has shown that MET RNA alterations acting an additive effects of MET overexpression are induced in the course of glioma evolution. In vitro and clinical studies indicate cells and patients harboring MET alterations have better response to MET inhibitors. Collectively, these data suggest that a subgroup of gliomas harboring MET alterations likely to have benefit from MET-targeted therapy.

Fusion genes as diagnostic and predictive biomarkers for tumor

“…Out of the six enrolled secondary GBM patients, two achieved partial response, two in stable disease, and two in progressed disease with no severe adverse events; this finding indicates the potential inhibitory effect of PLB and help determine the dose required for further investigation in Phase II clinical trial [83] . The median overall survival of the patients increased from 183 days to 466 days, and the 1-year survival rate increased from 8% to 67% [107] . More in-depth mechanism studies, identification of more targets, and more Phases 2 and 3 clinical trials are urgently needed.…”