# HER1-3 and Death Receptor protein folding as therapeutic vulnerabilities

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2023 · $209,624

## Abstract

Breast cancer remains a major killer of women due to the ineffectiveness of current drugs against
metastatic and drug-resistant cancers. Additionally, African American (AA) women suffer
disproportionately from breast cancer mortality in part because they develop the aggressive Triple-
Negative Breast Cancer (TNBC) subtype more frequently than other ethnic groups. Thus, agents
effective against drug-resistant and metastatic cancers and TNBCs may improve the survival of
breast cancer patients. These aggressive cancers evade cell death through a variety of mechanisms
including overactivation of the pro-survival HER-family of Receptor Tyrosine Kinases (RTKs),
including EGFR/HER1, HER2, and HER3 (HER1-3), and inactivation of pro-apoptotic signaling.
Tumors expressing HER1-3 are difficult to treat due to the partial redundancy among these receptors,
their oncogenic signaling as heterodimers, and their ability to aberrantly heterodimerize with non-HER
RTKs such as MET and IGF1R. Thus, resistance to current HER-targeted agents is a significant
clinical problem. Defective cancer cell apoptosis can result from inactivation of the TNF Receptor
Apoptosis Inducing Ligand (TRAIL)/Death Receptor 4/5 (DR4/5) pathway, which selectively kills
cancer cells, while not affecting normal cells. Tumor resistance to TRAIL and other DR4/5 agonists
results primarily from poor pharmacological properties of the agonists and the ability of cancer cells to
downregulate DR4/5. Consequently, agents that could inactivate the EGFR/HER2/HER3 signaling
axis and upregulate and activate DR4/5 independently of the TRAIL ligand may be efficacious against
breast cancers unresponsive to current medicines. Disulfide bond Disrupting Agents (DDAs) are a
new class of anti-cancer agents that induce regression of primary tumors and metastatic lesions of
drug-resistant patient-derived tumors in animal models. In addition to the structural uniqueness of
DDAs, recent studies indicate that DDAs are the first identified active site inhibitors of the Protein
Disulfide Isomerases (PDIs) ERp44 and AGR2. Further, DDA inhibition of the PDIs ERp44, AGR2,
and PDIA1 alters the disulfide bonding of HER1-3 and DR4/5, resulting in HER1-3 downregulation,
DR5 upregulation, and disulfide bond-mediated oligomerization and activation of DR4/5. The
objective of the current project is to move DDAs toward clinical trials. The two Specific Aims proposed
to achieve this objective are to 1) optimize DDA pharmacological properties and dosing for future
IND-enabling studies, and 2) validate biomarkers to predict tumor sensitivity to DDAs and to monitor
target engagement, and thoroughly evaluate any adverse effects of DDAs on normal tissues or
animal health. Based on their unique mechanisms of action and preclinical efficacy, we expect DDAs
to benefit breast cancer patients with treatment-refractory breast cancers.

## Key facts

- **NIH application ID:** 10721930
- **Project number:** 1R21CA277485-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Brian K. Law
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $209,624
- **Award type:** 1
- **Project period:** 2023-07-07 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721930

## Citation

> US National Institutes of Health, RePORTER application 10721930, HER1-3 and Death Receptor protein folding as therapeutic vulnerabilities (1R21CA277485-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10721930. Licensed CC0.

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