ABSTRACT High grade gliomas (HGGs), the most deadly malignant primary brain tumors in children, and are incurable with current therapies. To find mutations that drive formation and progression of pediatric HGGs (pHGGs), we genomically characterized over 25 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 and ALK fusions, found in more than 10% of pHGGs. 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 quickly developed resistant secondary tumors. Therefore, we are using our experiments MET fusion models, which include patient-derived pHGG tumor stem cells and xenografts as well as immunocompetent pHGG mouse models, to discover TKI resistance mechanisms. Already, our preliminary studies implicate cell-intrinsic innate immunity and inflammatory cytokine signaling in TKI drug tolerance and emergence of resistance among pHGG cells with MET fusions. To discover and study resistance mechanisms for MET and other RTK fusions in pHGG, we propose to two aims to 1) examine interactions between RTK fusions, RTK kinase inhibitors, and inflammatory cytokine signaling pathways and their effectors in vitro and in vivo in the brain using our robust MET fusion models, and to 2) test synergy between RTK kinase inhibitors and inflammatory pathway inhibition using pharmacologic and genetic approaches. We will use additional models of RTK fusions pHGGs to determine if our observations are generalizable among pHGGs with RTK fusions. The results of our research may lead to development of new combination precision treatment strategies for pHGG.