# A kinase-independent role for EGFR in p38MAPK suppression and S-phase progression in head and neck cancer

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $452,656

## Abstract

Head & Neck cancer (HNC) is the sixth most prevalent cancer worldwide, with over 600,000 new diagnoses
annually. Epidermal growth factor receptor (EGFR) is overexpressed in HNC and leads to poor prognosis.
Surprisingly, however, FDA-approved drugs that inhibit canonical EGFR signaling have had limited success in
the clinic, suggesting that disease progression relies on non-canonical mechanisms of EGFR signaling. We have
discovered such a non-canonical mechanism that consists of a hexameric receptor complex organized by
syndecan-4 (Sdc4) containing EGFR, the hepatocyte growth factor receptor homologue MST1R/RON, the
laminin-binding α3β1 and α6β4 integrins, and a second syndecan, Sdc2. RON and the cytoplasmic/nuclear
kinase c-Abl become constitutively activated when incorporated into this complex, suppressing activation of
p38MAPK that would otherwise cause immediate cessation of DNA synthesis and S-phase arrest. A peptide
(SSTNEGFR) that represents the extracellular docking site in Sdc4 competitively blocks the formation and signaling
of this receptor complex. Preliminary findings show that SSTNEGFR prevents the invasion of HNC cells and
induces their rapid cell cycle arrest. Whereas invasion relies on active EGFR, cell cycle progression depends
on EGFR but not its kinase activity, identifying a non-canonical EGFR signaling mechanism that is likely to be a
critical new therapeutic target in cancers such as HNC that overexpress EGFR. Remarkably, SSTNEGFR does
not cause cell cycle arrest in normal oral epithelial cells. Specifically, we plan to: (1) define the molecular
organization and signaling mechanism of the Sdc:RTK:ITG complex, focusing on molecular interactions used by
the two syndecans to assemble this complex, (2) identify the c-Abl and p38MAPK targets that govern stress
signaling and S-phase arrest, and (3) test the efficacy of SSTNEGFR against human HNC patient-derived
xenografts (PDXs) and the 4-NQO mouse model of HNC to determine at what stages in the initiation and
progression HNC the therapeutic is effective. Our goal will be to understand the molecular underpinnings of this
unique receptor complex, understand how it drives HNC and identify it as a possible new target for therapeutics
to treat HN disease.

## Key facts

- **NIH application ID:** 10137214
- **Project number:** 5R01DE028341-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** ALAN C RAPRAEGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $452,656
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137214

## Citation

> US National Institutes of Health, RePORTER application 10137214, A kinase-independent role for EGFR in p38MAPK suppression and S-phase progression in head and neck cancer (5R01DE028341-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10137214. Licensed CC0.

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