GENO-24ONCOGENIC PTPRZ1-MET FUSIONS PROMOTE MALIGNANT PROGRESS OF GLIOMAS

Abstract

We have recently identified a recurrent PTPRZ1-MET (ZM) fusions presenting in a subgroup of gliomas. Patients afflicted with ZM fusions harboring glioblastomas survived poorly relative to those afflicted with non-ZM harboring sGBMs. In the present study, we collected and analyzed a cohort of 339 patients with gliomas from 4 institutions (including 153 grade II, 104 grade III gliomas and 82 sGBM). We found 41 tumors with ZM fusions, of which 26 were sGBM (31.71%), 9 were grade II gliomas (5.88%) and 5 grade III gliomas (4.81%). RNA transcript fusing exon1and exon 2 of PTPRZ1 to exon 2 of MET (ZM1-2 and ZM 2-2) were the largest number and proportion. Two patients (grade II and III gliomas) without ZM fusions in each initial tumor, however, of which the fusions were detected in progressive tumors (sGBM). ZM fusions were associated with strong MET expression. The ZM fusion displays oncogenic activity when introduced into glioma cells or stereotactically transduced in the mouse brain by hyperactivated MET signaling. The ZM enhanced MET signaling can be significantly blocked by MET kinase inhibitors, Crizotinib and CAD-1001. The latter is a highly specific and single-target inhibitor of MET kinase under clinical investigation. ZM-transformed gliomas cells were more sensitive to the two inhibitors. These results suggest that PTPRZ1-MET fusions could potentially identify a subset of gliomas patients who would benefit from targeted MET kinase inhibition.