# c-Myc modulation and its implications in EGFR-targeted cancer therapy

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $399,207

## Abstract

SUMMARY
 An important milestone in the treatment of non-small cell lung cancer (NSCLC) is the discovery of
epidermal growth factor receptor (EGFR) activating mutations as an effective therapeutic target and the
successful development of EGFR tyrosine kinase inhibitors (EGFR-TKIs). AZD9291 (TAGRISSOTM or
osimertinib) represents a 3rd generation EGFR-TKI and an FDA-approved drug for patients with EGFR mutant
NSCLC that has become resistant to 1st generation EGFR-TKIs through the T790M mutation and for EGFR
mutation-positive advanced NSCLC as a front line treatment. Unfortunately, patients eventually relapse and
become resistant to AZD9291 in the clinic, resulting in disease progression. Thus, a better understanding of
the underlying mechanisms and development of effective strategies to overcome AZD9291 resistance is an
urgent and critical area of unmet need in the clinic. The C-MYC gene was the first Myc family member found in
the human genome and its product, c-Myc, functions as a transcription factor to regulate the expression of
many genes whose products are involved in the regulation of various physiological processes, such as cell
survival, proliferation, differentiation, metabolism and host immunity. MYC is genetically activated and/or
overexpressed in most types of human cancer including lung cancer and thus is a central driver of malignant
cellular growth and proliferation. c-Myc expression is associated with response or sensitivity of cancer cells to
chemotherapy or radiotherapy. However, no study has linked c-Myc to targeted therapy by third generation
EGFR-TKIs. Our strong preliminary data support the overall hypothesis that c-Myc modulation may play a
critical role in mediating therapeutic efficacy of AZD9291 against EGFRm NSCLC and the development of
acquired resistance to AZD9291; accordingly, targeting c-Myc will be an effective strategy to overcome
acquired resistance to AZD9291 and other EGFR-TKIs. This hypothesis will be tested by accomplishing the
following 3 specific aims: 1) To understand the mechanism(s) by which c-Myc is reduced in EGFR mutant
NSCLC cells by AZD9291 or other EGFR-TKIs; 2) To demonstrate the biological significance of c-Myc
suppression in EGFR-targeted therapy; and 3) To develop effective therapeutic regimens to overcome
acquired resistance to AZD9291 by targeting c-Myc. The objectives of this study are to understand the
mechanisms by which AZD9291 and other EGFR-TKIs decrease c-Myc levels, to demonstrate the biological
significance of c-Myc suppression during EGFR-targeted cancer therapy; and to develop effective strategies to
overcome acquired resistance to AZD9291 by targeting c-Myc. This proposal is of high scientific and
translational significance. The outcomes of this study can be immediately translated to the clinical treatment of
NSCLC patients with acquired resistance to AZD9291 or other EGFR-TKIs.
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## Key facts

- **NIH application ID:** 10049578
- **Project number:** 1R01CA245386-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Shi-Yong Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,207
- **Award type:** 1
- **Project period:** 2020-07-07 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049578

## Citation

> US National Institutes of Health, RePORTER application 10049578, c-Myc modulation and its implications in EGFR-targeted cancer therapy (1R01CA245386-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10049578. Licensed CC0.

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