# EGFR signaling network adaptations to overcome RAS-induced membrane stress in glioblastoma

> **NIH NIH U54** · UNIVERSITY OF VIRGINIA · 2024 · $352,763

## Abstract

SUMMARY
The most common genetic alteration in glioblastoma (GBM) is amplification of the receptor tyrosine kinase
EGFR. In GBM, some amplified EGFR further mutates to yield exon-deleted EGFRvIII, which is constitutively
active and endocytosis impaired, thereby signaling to effector pathways that favor survival over proliferation. It
is not clear why EGFRvIII is specifically selected for in this disease, but GBM cells poorly tolerate unbridled
signaling from the EGFR effector RAS. Chronic RAS signaling places an oncogene-induced stress on cell
membranes that gives rise to excessive micropinocytosis and vacuolization, concluding with an alternative
form of cell death called methuosis. The objective of this work is to reconcile EGFR amplification and
EGFR/RAS-induced membrane stress through EGFRvIII and the signaling intermediates they share.
Preliminary evidence suggests that EGFRvIII may achieve stress-relieving signaling adaptations by rewiring
the network of protein-protein interactions at different subcellular locations within GBM cells. Our hypothesis is
that EGFRvIII is a GBM-specific adaptive mechanism for overcoming methuosis. We will build a computational
model of EGFR/EGFRvIII signaling that tests this hypothesis by accounting for the network of protein
interactions and signaling relevant for the methuosis phenotype. The specific aims are to 1) define the key
intermolecular interactions in the EGFR signaling network and mechanistically predict the consequences of
network adaptations to EGFRvIII expression; 2) map differential EGFR signaling network activation among
glioblastoma cells to the methuosis phenotype through a hybrid mechanistic and data-driven computational
model; and 3) test model predictions about signaling control of methuosis in vitro and in vivo using new tools to
monitor RAS-ERK and AKT activities concurrently and noninvasively. This project brings together a team of
investigators with complementary expertise in mechanistic and data-driven computational models of receptor-
mediated signaling, protein-protein interactions, in vivo transplantations of GBM, and treatment of GBM
patients using investigational approaches. By quantitatively testing the hypothesis about EGFRvIII as a key
regulator of oncogene-induced plasma membrane stress in glioblastoma, our collaborative project holds
promise for identifying conceptually new approaches for driving alternative cell-death phenotypes in a highly
chemotherapy-resistant cancer for which durable therapies are desperately needed.

## Key facts

- **NIH application ID:** 10903899
- **Project number:** 5U54CA274499-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Matthew J Lazzara
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $352,763
- **Award type:** 5
- **Project period:** 2022-09-12 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903899

## Citation

> US National Institutes of Health, RePORTER application 10903899, EGFR signaling network adaptations to overcome RAS-induced membrane stress in glioblastoma (5U54CA274499-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10903899. Licensed CC0.

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