# Stress responses drive resistance and shape tumor evolution in EGFR mutant lung cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $493,346

## Abstract

ABSTRACT
Resistance to targeted therapy is a major challenge in oncology and barrier improving patient survival. As a
paradigm-defining example, EGFR tyrosine kinase inhibitors (TKIs) are effective in many EGFR-mutated non
small-cell lung cancer patients. However, promising initial responses in these patients are always followed by
the development of acquired resistance, most often a lethal event. The cellular basis for this stems from an
incomplete initial response forming a reservoir of residual disease caused by tumor cell persistence and drug
tolerance, through poorly understood mechanisms. In extensive preliminary data we discovered that the
persistence and drug tolerance of EGFR-mutant lung cancer cells is dependent on a mitotic stress response
elicited by drug treatment. Drug tolerant tumor cells are dependent on continued mitotic stress signaling, and
are vulnerable to Aurora Kinase inhibitors in vitro and in vivo. Tumor samples from patients progressing on
EGFR inhibitors frequently displayed evidence of ongoing stress signaling, often co-occurring with other
genetic changes commonly associated with drug resistance. Here we seek to mechanistically dissect how this
stress signaling aids in tumor cell persistence and acquired resistance and the role it plays in shaping tumor
evolution after therapy. We will test the hypothesis that stress from acute oncogene withdrawal drives the
unexplained and key features of drug tolerance and residual disease during EGFR TKI treatment that is:
cellular adaptation and resistance to apoptosis (Aim 1) and the catalysis of genetic evolution leading to the de
novo gain of resistance causing mutations (Aim 2). Finally, this knowledge will be used to identify new
therapeutic strategies to forestall tumor evolution by limiting stress signaling (Aim 3). To address this
hypothesis, our team consists of experts in lung cancer, systems biology and clinical translation and will use
innovative new single cell approaches, live cell imaging, state-of-the-art animal and organoid models and
patient samples. Our goal is to lay the mechanistic groundwork that shifts the paradigm from the current
reactionary approach of targeting acquired resistance after it emerges to a proactive approach that targets
sources of residual disease to prevent acquired resistance.

## Key facts

- **NIH application ID:** 10329992
- **Project number:** 5R01CA238236-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sourav Bandyopadhyay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $493,346
- **Award type:** 5
- **Project period:** 2020-02-20 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329992

## Citation

> US National Institutes of Health, RePORTER application 10329992, Stress responses drive resistance and shape tumor evolution in EGFR mutant lung cancer (5R01CA238236-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10329992. Licensed CC0.

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