# Dissecting EGFR Inhibitor Resistance in Glioblastoma through genome-wide CRISPR screening

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $15,696

## Abstract

PROJECT SUMMARY/ABSTRACT
Drug resistance represents a major problem in glioblastoma (GBM), the most common and aggressive
malignant brain tumor in adults. GBM cells that proliferate and survive through aberrant activation of kinase
signaling pathways are believed to avoid the deleterious effects of therapeutic kinase inhibition through
utilization of alternative signaling and metabolic pathways. The epidermal growth factor receptor (EGFR)
represents a compelling example to dissect this question because at least 40% of human GBMs harbor an
EGFR alteration, and inhibitors of this pathway (EGFRi) have been largely ineffective thus far. Despite
considerable progress in understanding EGFRi resistance in other cancers (most notably, non-small cell lung
cancer), mechanisms of EGFRi resistance in GBM remain poorly understood. To identify novel mechanisms of
EGFR kinase inhibitor resistance in GBM, I have performed genome-scale clustered regularly interspaced
short palindromic repeats (CRISPR) library screens in several EGFR-mutant GBM cell lines in the presence
and absence of the pan-ErbB inhibitor neratinib. Loss of multiple members of the amino-acid sensing pathway
(e.g., GCN2, GCN1L1) were associated with neratinib resistance in these cell lines. I have also observed that
acute EGFR inhibition induces the amino acid sensing pathway (e.g., phosphorylation of EIF2a and ATF4
expression). Based on these results, I hypothesize that EGFR inhibition induces a state of amino acid
starvation and activation of the integrated stress response (ISR) which can be bypassed by loss of GCN2 or
other related genes in the ISR pathway. I propose to elucidate this novel mechanism of EGFR inhibitor
resistance through a series of biochemical and genetic experiments and further explore its broader biological
significance in genetically characterized, patient-derived human GBM models. My overall goal is to further
understand the molecular and cellular consequences of EGFR inhibition, with the goal of designing more
effective therapeutic strategies for patients with EGFR-altered GBM.

## Key facts

- **NIH application ID:** 10098016
- **Project number:** 5F31CA239401-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Colin Patrick Tang
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $15,696
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-06-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098016

## Citation

> US National Institutes of Health, RePORTER application 10098016, Dissecting EGFR Inhibitor Resistance in Glioblastoma through genome-wide CRISPR screening (5F31CA239401-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10098016. Licensed CC0.

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