# Co-targeting S6 and TAM kinases in PTEN-deficient glioblastoma

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2024 · $400,209

## Abstract

Co-targeting S6 and TAM kinases in PTEN-deficient glioblastoma
Project Summary
The ribosomal S6 protein kinases (S6Ks) are activated in response to loss of the tumor suppressor PTEN in
glioblastoma and other cancers of solid and hematopoietic tissues. We previously reported that genetic
inactivation of S6K1 counteracts the metabolic and anti-apoptotic effects of PTEN loss in cancer, in agreement
with several observations in comparable settings. Recently we investigated pharmacological inhibitors that
target S6K1, which led to the identification of a PTEN-specific vulnerability to combination inhibition of S6K1
together with the TAM family of tyrosine kinases. The TAM family of tyrosine is named for its members, which
are TYRO3, AXL, and MERTK. TAM tyrosine kinases are highly targetable in oncology, as there are several
late-stage clinical trial and FDA-approved tyrosine kinase inhibitors that have activity against all three
members. In a validation phase using genetic approaches to investigate the requirements for PTEN-selective
cytotoxicity, results revealed that inactivation of TAM kinases is sufficient to sensitize PTEN-deficient cells to
inhibition of S6K1. In the present research application, we propose to extend the genetic analysis of S6 and
TAM kinases to elucidate the mechanisms that relate the kinases in the setting of PTEN-deficient glioblastoma.
Experiments will make use of CRISPR Cas9 genome editing technologies to inactivate the S6K and TAM
kinase family members, alone or in combination, while determining signaling and metabolic effects. Model
systems will employ patient-derived tumor samples to assess the generality and applicability of genetic results
to physiologic functions of glioblastoma tumors/cells. We anticipate that the results will provide the
mechanistic framework that will inform the development of targeted therapeutic strategies affecting the S6Ks
and TAMs themselves, or signaling components that are part of their pathways.

## Key facts

- **NIH application ID:** 10740887
- **Project number:** 5R01CA239657-05
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** David R Plas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $400,209
- **Award type:** 5
- **Project period:** 2019-12-11 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740887

## Citation

> US National Institutes of Health, RePORTER application 10740887, Co-targeting S6 and TAM kinases in PTEN-deficient glioblastoma (5R01CA239657-05). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10740887. Licensed CC0.

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