# Yale SPORE in Lung Cancer (YSILC): The Biology and Personalized Treatment of Lung Cancer

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

## Abstract

SUMMARY
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. To investigate this hypothesis, we
intend to employ our in situ chromatin tracing approach to examine how the 3D genome reorganizes in the
context of EGFR inhibitor resistance using human LUAD cancer cell lines, patient biospecimens, and PDX
models, extending studies on the epigenetic basis of TKI resistance in the parent P50 award to an entirely new
layer of epigenetic information, the 3D genome. By utilizing our established analytical methods, we will decipher
the resistance mechanisms encoded by the 3D genome and validate their functional significance through genetic
and pharmacological experiments in both cell culture and animal models. These studies will foster the
development of novel prognostic and predictive biomarkers of drug resistance based on single-cell 3D genome
conformations and aid in the identification of novel therapeutic targets to overcome drug resistance.

## Key facts

- **NIH application ID:** 10918840
- **Project number:** 3P50CA196530-10S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Roy S Herbst
- **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/10918840

## Citation

> US National Institutes of Health, RePORTER application 10918840, Yale SPORE in Lung Cancer (YSILC): The Biology and Personalized Treatment of Lung Cancer (3P50CA196530-10S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10918840. Licensed CC0.

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