# Mechanisms of RIOK2 function in glioblastoma

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $337,995

## Abstract

PROJECT SUMMARY
Glioblastomas (GBMs), the most common and deadly primary malignant brain tumors, frequently display
mutations that activate receptor tyrosine kinases (RTKs) and the Pi-3 kinase-Akt (PI3K) signaling pathway.
Yet, to date, drugs that directly inhibit RTK and/or PI3K signaling have proven ineffective in treatment of GBM.
Our research program uses complementary experimental model systems, including patient-derived primary
GBM stem cell cultures and novel GBM models in Drosophila melanogaster, to identify and interrogate genetic
and cellular processes that underlie glial tumorigenesis. Using our GBM model systems, we identified RIOK2,
a highly conserved atypical serine-threonine kinase, and our results revealed that, in GBMs, RIOK2 becomes
overexpressed in response to RTK-PI3K signaling to drive tumor cell proliferation and survival, and that RIOK2
knockdown in RTK-PI3K dependent GBM cells inhibits proliferation and elicits apoptosis. Our preliminary data
also indicate that, in both Drosophila and human GBM models, inhibition of RIOK2 catalytic activity strongly
counteracts RTK-PI3K-driven transformation. In contrast, loss or inhibition of RIOK2 activity in normal human
or Drosophila glial progenitor/stem cells does not elicit cell death and does not dramatically affect cell
proliferation. Thus, RTK-PI3K mutant tumor cells, but not normal glial cells, are dependent on RIOK2 activity
for their growth and survival. Based on our preliminary data, we hypothesize that RIOK2 drives GBM by
phosphorylating and activating RNA-binding proteins to promote the translation of oncogenic target mRNAs,
and that RIOK2 differentially promotes the growth and survival of GBM cells by stimulating the translation of
oncogenic mRNAs that are expressed as a consequence of gliomagenic RTK and PI3K signaling. This
proposal focuses two aims designed to Aim 1) Determine the mechanisms of interaction between RIOK2 and
its associated RNA-binding proteins, and Aim 2) Determine if RIOK2 activity specifically promotes translation of
select target mRNAs in tumor cells. This project may reveal new mechanisms that drive tumorigenesis, and
establish a basis for developing RIOK2 inhibitors for potential targeted treatment for GBM.

## Key facts

- **NIH application ID:** 9842017
- **Project number:** 5R01NS100967-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Renee D Read
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,995
- **Award type:** 5
- **Project period:** 2017-03-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842017

## Citation

> US National Institutes of Health, RePORTER application 9842017, Mechanisms of RIOK2 function in glioblastoma (5R01NS100967-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842017. Licensed CC0.

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