MET kinase fusions in pediatric glioblastoma

摘要

ABSTRACT High grade gliomas (HGGs), the most deadly malignant primary brain tumors in children, are incurable with current therapies. To find mutations that drive formation and progression of pediatric HGGs (pHGGs), we genomically characterized patient tumors, and we identified fusion mutations in the MET and ALK receptor tyrosine kinases. Recent comprehensive analyses show that RTK fusions are found in up to 40% of pHGGs, and among the most common are MET, ALK, and NTRK fusions. Our and others’ data show that for many RTK fusions, in which the C-terminal kinase domain is fused to N-terminal regions of other proteins that are normally highly expressed in neuro-glial stem/progenitor cells, indicating that MET fusions are likely overexpressed as a consequence of developmental programs. Our results show that RTK fusions, such as the MET fusions, create constitutively active kinases capable of transforming neural stem cells into pHGG-like tumors. FDA-approved small molecule tyrosine kinase inhibitors (TKIs) exist that penetrate the blood-brain barrier that may benefit pHGG patients with MET and ALK fusions as well as other RTK fusions, and these TKIs are being tested in patients with RTK fusions on an investigational basis. However, despite initial responses, MET fusion pHGG patients can develop resistant tumors. Therefore, to discover TKI resistance mechanisms, we have created our experimental immunocompetent mouse pHGG models for tumors with MET and ALK fusions. Already, our preliminary studies implicate cell-intrinsic innate immunity and inflammatory cytokine signaling pathways in drug tolerance and resistance among pHGG cells with MET fusions. To discover and study resistance mechanisms and to determine if biological sex affects how pHGGs with RTK fusions, we propose to two aims to 1) examine expression and activation of innate immunity pathways in pHGGs with RTK fusions and 2) examine sex differences in innate immunity pathways function in pHGGs with RTK fusions. The results of our research may lead to development of new combination precision treatment strategies for pHGG. 1