# Interactions between inflammatory and oncogenic signaling pathways in GBM

> **NIH VA I01** · VA NORTH TEXAS HEALTH CARE SYSTEM · 2021 · —

## Abstract

Inhibition of epidermal growth factor receptor (EGFR) signaling is an important approach to the targeted
treatment of cancer. However, although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is
primarily effective only in a limited number of lung cancers that express specific EGFR mutations and are
oncogene addicted. Thus, the ability to render cancer cells with primary EGFR resistance sensitive to EGFR
inhibition is potentially of enormous clinical value, given the wide prevalence of EGFR overexpressing cancers
with primary resistance to EGFR inhibition. EGFR wild type (EGFRwt) is the most common EGFR type
expressed in human cancer. However, tumors expressing EGFRwt are not oncogene addicted and EGFR
inhibition is generally ineffective as a treatment. Here, we propose a mechanism that mediates primary
resistance to Erlotinib in glioblastoma (GBM) cells and a strategy to overcome it. EGFR gene amplification and
mutation are common in GBM, but EGFR inhibition has not been effective in treating this tumor. We propose
that the primary resistance of EGFR overexpressing GBMs results from a rapid adaptive response that
prevents cell death from a sudden loss of EGFR signaling. This adaptive response can be detected in glioma
cells expressing either EGFRwt or the oncogenic EGFRvIII mutant. Our preliminary data indicate that in
glioma cells expressing either EGFRwt or EGFRvIII, Erlotinib triggers a rapid homeostatic response that
involves activation of the RTK Axl and downstream activation of ERK. We propose that JNK acts as a master
regulator of Erlotinib-triggered survival signals. Thus, Erlotinib exposure leads to increased TNF secretion,
leading to activation of JNK. JNK activation leads to activation of Axl via increased secretion of GAS6, the
ligand for Axl, and Axl induced ERK activation. Thus, we propose that primary resistance to EGFR inhibition in
glioma cells results from activation of a TNF-JNK-Axl-ERK pathway. In Specific Aim 1: We elucidate the
mechanism of Erlotinib-induced JNK activation. Erlotinib induced JNK activation is important because JNK
triggers key survival signals as a response to EGFR inhibition. WE hypothesize that TNF plays a key role in
Erlotinib induced JNK activation. In Specific Aim 2 we examine the mechanisms mediating primary resistance
to Erlotinib in glioma cells and examine the hypothesis that JNK activation results in activation the receptor
tyrosine kinase Axl and downstream activation of ERK, and that this JNK-Axl-ERK axis mediates primary
resistance to Erlotinib. In Specific Aim 3 we examine the biological effect of combined inhibition of EGFR and
TNF or JNK or Axl in a preclinical mouse model examining the hypothesis that interruption of adaptive survival
signaling triggered by EGFR inhibition will transform cancers with primary resistance into cancers that can be
effectively treated by EGFR inhibition. Since both EGFR and TNF inhibitors are in clinical use, this approach
could be rapidly teste...

## Key facts

- **NIH application ID:** 10266003
- **Project number:** 5I01BX002559-08
- **Recipient organization:** VA NORTH TEXAS HEALTH CARE SYSTEM
- **Principal Investigator:** AMYN HABIB
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10266003

## Citation

> US National Institutes of Health, RePORTER application 10266003, Interactions between inflammatory and oncogenic signaling pathways in GBM (5I01BX002559-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10266003. Licensed CC0.

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