# Project 2: Mechanism-based approaches to counter TKI resistance in EGFR mutant lung cancer

> **NIH NIH P50** · YALE UNIVERSITY · 2023 · $392,909

## Abstract

PROJECT SUMMARY
Targeted therapies have completely transformed the landscape for diagnosis and treatment of metastatic lung
cancer. Despite this success, targeted therapies are not curative and acquired resistance is a major
impediment to cures or durable responses for patients treated with these therapies. A paradigm for the
success of targeted therapies in lung cancer, comes from Epidermal Growth Factor Receptor (EGFR) mutant
lung cancer. Mutations in exons encoding the tyrosine kinase domain of EGFR are found in approximately 10-
15% of lung adenocarcinomas in the US. These mutations confer sensitivity to tyrosine kinase inhibitors (TKIs)
and four TKIs (erlotinib, gefitinib, afatinib and, most recently, osimertinib) are currently approved for the first-line
treatment of EGFR mutant lung cancer. Acquired drug resistance, however, is a major challenge with all of these
TKIs including osimertinib, but we have very limited knowledge of the mechanisms of resistance to
osimertinib given its recent adoption in the clinic. Without knowledge about resistance mechanisms, optimal
post-osimertinib treatment strategies remain to be defined. Data from our labs and others indicate that
osimertinib resistance can arise through both EGFR-dependent mechanisms involving several different types of
EGFR mutation and EGFR-independent mechanisms – frequently epigenetic in origin – that are poorly
understood. Very little is known about the molecular context(s) in which these resistance mechanisms
emerge, their frequency, biochemistry and how to target them pharmacologically. Given the speed of
adoption of osimertinib as 1st line therapy, there is an urgent need to identify these mechanisms and resulting
vulnerabilities. We propose to leverage our collective expertise in lung cancer biology, mouse models,
resistance to targeted therapies and EGFR structural biology to address these issues. Using unique in vitro and
in vivo models and patient resources of acquired resistance to osimertinib, innovative genomic and biochemical
tools we will: 1) Identify molecular features and new therapeutic vulnerabilities of osimertinib-resistance EGFR
variants. 2) Establish mutant EGFR heterodimerization patterns and determine whether these can be leveraged
therapeutically to overcome osimertinib resistance; 3) Identify epigenetic processes that confer TKI resistance.
Our studies will yield a comprehensive understanding of osimertinib resistance and insight with which to develop
new mechanism-based approaches to target osimertinib-resistant tumors – an urgent unmet clinical need.

## Key facts

- **NIH application ID:** 10690069
- **Project number:** 5P50CA196530-09
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** KATERINA Abigail POLITI
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $392,909
- **Award type:** 5
- **Project period:** 2015-08-26 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690069

## Citation

> US National Institutes of Health, RePORTER application 10690069, Project 2: Mechanism-based approaches to counter TKI resistance in EGFR mutant lung cancer (5P50CA196530-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10690069. Licensed CC0.

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