# Modulation of death receptor 4 in EGFR-targeted cancer therapy

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $115,235

## Abstract

SUMMARY
Targeting epidermal growth factor receptor (EGFR) activating mutations, 90% of which present as an exon 19
deletion (Del19) or exon 21 point mutation (L858R), with first generation EGFR tyrosine kinase inhibitors
(EGFR-TKIs; e.g., erlotinib and gefitinib) and the T790M resistance mutation with third generation EGFR-TKIs
(e.g., AZD9291; TAGRISSOTM or osimertinib) has provided significant clinical benefit in patients with non-small
cell lung cancer (NSCLC) harboring these mutations. Unfortunately, resistance to these EGFR-TKIs occurs in
the clinic, resulting in disease progression. Hence, understanding the underlying mechanisms and developing
effective strategies to overcome EGFR-TKI resistance is highly desirable and urgently needed in the clinic.
Death receptor 4 (DR4; also known as TRAIL-R1 or TNFRSF10A) is a cell surface receptor for tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL). It is generally thought that its activation, upon binding to
TRAIL, induces apoptosis; this function is recognized as a critical mechanism of immunosurveillance against
cancer cells. However, whether DR4 exerts other as yet unknown biological functions is unclear. Our
preliminary data demonstrated that EGFR inhibition with several EGFR inhibitors including AZD9291, CO1686,
and erlotinib substantially decreased DR4 levels primarily in EGFR-TKI-sensitive EGFR-mutant NSCLC cell
lines; this DR4 reduction is tightly associated with ERK suppression and induction of apoptosis in the tested
cell lines. Unexpectedly, knockdown of DR4 augments TRAIL-induced apoptosis and also enhances AZD9291-
induced apoptosis. This proposal thus will test the overall hypothesis that suppression of DR4 expression is an
on-target consequence of EGFR inhibition and has critical impact on both early and long-term therapeutic
efficacy of EGFR-targeted therapy. This hypothesis will be tested by accomplishing the following specific aims:
(1) to demonstrate the mechanism(s) by which EGFR inhibitors suppress DR4 expression; (2) to understand
the biological significance of DR4 suppression in EGFR-targeted cancer therapy; and (3) to elucidate the effect
of DR4 downregulation on the efficacy of EGFR-targeted therapy using preclinical NSCLC patient-derived
xenografts (PDXs) and samples from NSCLC patients treated with EGFR-TKIs. The objectives of this proposal
are to demonstrate the molecular mechanism underlying DR4 reduction caused by EGFR inhibition, to
understand the biological significance of DR4 suppression in EGFR-targeted cancer therapy, and to validate
DR4 downregulation in clinical specimens from NSCLC patients receiving EGFR-TKIs. We believe that the
outcomes of this proposal will be of high translational significance with immediate impact on EGFR-targeted
cancer therapy in the clinic.
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## Key facts

- **NIH application ID:** 10135576
- **Project number:** 3R01CA223220-04S1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Shi-Yong Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $115,235
- **Award type:** 3
- **Project period:** 2018-07-09 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135576

## Citation

> US National Institutes of Health, RePORTER application 10135576, Modulation of death receptor 4 in EGFR-targeted cancer therapy (3R01CA223220-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135576. Licensed CC0.

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