# MET kinase fusions in pediatric glioblastoma

> **NIH NIH R21** · EMORY UNIVERSITY · 2022 · $21,910

## Abstract

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.
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## Key facts

- **NIH application ID:** 10690229
- **Project number:** 3R21NS116639-01A1S1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Renee D Read
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $21,910
- **Award type:** 3
- **Project period:** 2022-09-27 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690229

## Citation

> US National Institutes of Health, RePORTER application 10690229, MET kinase fusions in pediatric glioblastoma (3R21NS116639-01A1S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10690229. Licensed CC0.

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