# The role of Nrf2 in mediating resistance to EGFR inhibition in glioblastoma

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $377,049

## 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. Aberrant epidermal growth factor receptor (EGFR) signaling is
common in glioblastoma (GBM). GBM is a devastating disease and, even with the best treatment, the
prognosis is dismal. No targeted treatment is effective in GBM. EGFR gene amplification and mutation are
common in GBM and multiple trials of EGFR inhibition in GBM have been conducted. However, EGFR
inhibition has not been successful in GBM. The failure of targeted treatments in GBM has led to an intensive
effort to understand mechanisms that mediate resistance to targeted treatment. Here, we propose a
mechanism that mediates primary resistance to EGFR inhibition in GBM and a strategy to overcome it. We
propose that the primary resistance of EGFR expressing 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 transcription factor Nrf2 signaling network. Nrf2 regulates key downstream signaling
networks that are critical mediators of therapeutic resistance to EGFR inhibition in GBM. Our preliminary data
indicate that a combined inhibition of EGFR and Nrf2 overcomes the primary resistance of GBMs to EGFR
inhibition in cell culture as well as in an orthotopic model of GBM. In Specific Aim 1: we examine the effector
mechanisms downstream of Nrf2 that mediate mediating primary resistance to EGFR inhibition in glioma cells
In Specific Aim 2 we examine the mechanisms that regulate activation of Nrf2 in response to EGFR inhibition
in GBM. In Specific Aim 3 we examine the biological effect of combined inhibition of EGFR and Nrf2 or
inhibition of key signaling networks downstream of Nrf2 in a preclinical mouse orthotopic model examining the
hypothesis that interruption of adaptive survival signaling triggered by EGFR inhibition will transform GBMs
with primary resistance into cancers that can be effectively treated by EGFR inhibition. Since both EGFR and
Nrf2 inhibitors are in clinical use, this approach could be rapidly tested in patients. The proposal addresses
critical unmet needs in the management of GBM, and could have a transformative impact on the way GBM is
treated.

## Key facts

- **NIH application ID:** 10168484
- **Project number:** 5R01CA244212-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** AMYN HABIB
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,049
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168484

## Citation

> US National Institutes of Health, RePORTER application 10168484, The role of Nrf2 in mediating resistance to EGFR inhibition in glioblastoma (5R01CA244212-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10168484. Licensed CC0.

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