# Overcoming Drug Resistance in HER2-positive Breast Cancer

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2020 · $450,628

## Abstract

HER2 is an oncogenic receptor tyrosine kinase (RTK). It is overexpressed in about 20% breast cancer (BC)
due to gene amplification, known as HER2-positive BC (HER2+ BC). Several HER2 inhibitors are available
clinically and have significantly improved disease outcome. However, primary and acquired drug resistance
is common. Most patients with advanced disease show disease progression after some time on treatment.
Drug resistance is a major unresolved problem in HER2+ BC, and our long-term goal is to find a solution to
this problem. In this project, we propose to investigate a recombinant human protein, i.e., PEPDG278D, for
overcoming drug resistance in HER2+ BC. PEPDG278D is an enzymatically inactive mutant of peptidase D
(also known as prolidase). Exogenously-administered PEPDG278D binds to HER2 and its family member
EGFR, and in cancer cells overexpressing the RTKs, PEPDG278D disrupts their signaling units, directs them
for lysosomal degradation, and inhibits the growth of the cells in vitro and in vivo. PEPDG278D inhibits HER2+
BC cells that are resistant to current HER2 inhibitors in vitro and in vivo. Yet, PEPDG278D is well tolerated in
mouse studies and shows little effect on HER2 and EGFR in normal tissues where expression of the RTKs
is very low. Cancer cells lacking HER2 and EGFR are insensitive to PEPDG278D as well. The objectives of
this proposal are: 1) to determine the therapeutic activity and mechanism of action of PEPDG278D in HER2+
BC, and 2) to assess PEPDG278D safety and to understand how PEPDG278D spares HER2 and EGFR in
normal cells. The central hypothesis is that PEPDG278D targets HER2 and EGFR specifically and its unique
binding mode enables it to target overexpressed HER2 and EGFR strongly and selectively, thereby
inhibiting drug-resistant HER2+ BC without causing toxicity. The rationale for the proposal is that completion
of the research may propel PEPDG278D into clinical evaluation. We propose three specific aims to test the
hypothesis: 1) to elucidate the target specificity of PEPDG278D, 2) to assess its therapeutic activity and
mechanism of action, and 3) to determine its target selectivity and how it spares HER2 and EGFR in normal
cells. An innovative combination of experimental methods will be used, including but not limited to isogenic
cells, cells and tumors carrying clinically verified molecular changes that confer resistance to current HER2
inhibitors, primary normal human cells and humanized mice. The proposed research is significant, because
it addresses a major problem in HER2+ BC, i.e., drug resistance. Expected outcome of this work includes:
1) showing that HER2 and EGFR are the sole therapeutic targets of PEPDG278D; 2) showing that PEPDG278D
inhibits HER2+ BC resistant to current HER2 inhibitors and the underlying mechanisms; 3) showing that
HER2 remains a critical therapeutic target in drug-resistant HER2+ BC; and 4) showing that PEPDG278D is
non-toxic to normal cells and tissues and understanding the molecu...

## Key facts

- **NIH application ID:** 10051017
- **Project number:** 1R01CA244601-01A1
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** YUESHENG ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,628
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051017

## Citation

> US National Institutes of Health, RePORTER application 10051017, Overcoming Drug Resistance in HER2-positive Breast Cancer (1R01CA244601-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10051017. Licensed CC0.

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