# Targeted Degradation of EGFR and HER2 in NSCLC

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $503,685

## Abstract

Project Summary/Abstract
Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), is an oncogenic driver that is
frequently overexpressed or mutated in non-small cell lung cancer (NSCLC). Many EGFR inhibitors are
used to treat NSCLC, but drug resistance is common. Necitumumab (Neci), an EGFR-directed monoclonal
antibody, is approved for a subset of NSCLC harboring wild type (WT) EGFR but its efficacy is very limited.
Patients whose tumors harbor mutated EGFR often derive significant benefit from EGFR tyrosine kinase
inhibitors (TKIs), but resistance invariably develops. Mechanism of resistance to EGFR inhibitors is complex
and not fully known. Our objective in this project is to evaluate a new agent for overcoming drug resistance
in NSCLC using preclinical models. The project builds on our recent discovery that a recombinant human
protein, PEPDG278D, induces the degradation of EGFR and HER2 by binding to their extracellular domain.
HER2 is closely related to EGFR and a key contributor to drug resistance in NSCLC. PEPDG278D is an
enzymatically inactive mutant of human peptidase D, also known as prolidase important for collagen
metabolism. We also find that PEPDG278D induces the degradation of mutated EGFR and HER2 that occur in
NSCLC and strongly inhibits NSCLC cells and tumors resistant to current EGFR inhibitors. We envision that
targeted degradation of EGFR and HER2 is more effective than only inhibiting the activation or activity of
their tyrosine kinase, as kinase-independent functions are also important for their oncogenic signaling. Our
overall hypothesis is that NSCLC cells and tumors resistant to current EGFR inhibitors are vulnerable to
targeted degradation of EGFR and HER2 by PEPDG278D and that PEPDG278D induces the degradation of not
only WT EGFR and HER2 but also a broad spectrum of clinically relevant mutants. We will test the
hypothesis in three specific aims: 1) to assess PEPDG278D for inhibition of oncogenic signaling and antitumor
activity in NSCLC cells and tumors expressing WT EGFR, and to compare PEPDG278D to Neci; 2) to
determine if PEPDG278D inhibits the oncogenic signaling of a broad spectrum of EGFR and HER2 mutants in
NSCLC cells by inducing their degradation and to compare PEPDG278D to osimertinib (Osi) which is a third
generation EGFR TKI and the preferred EGFR TKI for NSCLC patients; and 3) to determine if Osi-resistant
NSCLC cells and tumors are sensitive to PEPDG278D and if combining the two agents enhances therapeutic
outcome. PEPDG278D and Osi complement each other mechanistically in targeting EGFR mutants. The
proposed research is significant, because it addresses drug resistance in NSCLC which remains a major
clinical problem. We expect 1) to show that PEPDG278D is therapeutically superior to Neci and Osi; 2) to
establish the novel concept that inducing the degradation of EGFR and HER2 is an effective strategy for
overcoming drug resistance in NSCLC. These findings may generate strong enthusiasm...

## Key facts

- **NIH application ID:** 10979401
- **Project number:** 1R01CA285391-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** YUESHENG ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $503,685
- **Award type:** 1
- **Project period:** 2024-07-18 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979401

## Citation

> US National Institutes of Health, RePORTER application 10979401, Targeted Degradation of EGFR and HER2 in NSCLC (1R01CA285391-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10979401. Licensed CC0.

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