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

> **NIH NIH P50** · YALE UNIVERSITY · 2024 · $218,588

## Abstract

Although tyrosine kinase inhibitors (TKIs) have significantly transformed the treatment of EGFR mutant lung adenocarcinoma (LUAD), their effectiveness is often limited by acquired drug resistance. In a significant portion of the cases, resistance arises without detectable mutations or changes in gene copy numbers, suggesting 
epigenetic mechanisms underlie resistance. Recent evidence indicates that the three-dimensional (3D) folding organization of the genome regulates the cancer cell epigenome, which can activate oncogenes, inactivate tumor suppressor genes, and promote metastasis and stemness. However, it remains unknown whether and how 3D genome alternations contribute to resistance to targeted therapies. To address this knowledge gap, we have developed a chromatin tracing strategy to visualize the 3D genome organization at the single-cell level in the native cancer tissue context. We applied this method to a reliable mouse model of LUAD driven by the oncogene 
Kras and identified characteristic alterations in the 3D genome during cancer development, including a notable structural bottleneck in LUAD progression. Moreover, we demonstrated that the 3D genome encodes distinct cancer states within individual cells and uncovers novel genetic dependencies in LUAD, highlighting the critical 
role of 3D genome reorganization in LUAD development. Based on these findings, we propose that structural changes in the 3D genome similarly mediate resistance to targeted therapies.

## Key facts

- **NIH application ID:** 11146985
- **Project number:** 3P50CA196530-10S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** KATERINA Abigail POLITI
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $218,588
- **Award type:** 3
- **Project period:** 2015-08-26 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11146985

## Citation

> US National Institutes of Health, RePORTER application 11146985, Project 2: Mechanism-based approaches to counter TKI resistance in EGFR mutant lung cancer (3P50CA196530-10S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11146985. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*