# Resolving epigenetic determinants of cellular plasticity programs in non-small cell lung cancer

> **NIH NIH F99** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $43,550

## Abstract

SUMMARY
Pioneering research in cancer biology over the past four decades has uncovered a repertoire of oncogenes and
tumor suppressors that initiate and maintain tumorigenesis across diverse cancer types. Such genetic alterations
constitute an important aspect of intra-tumor heterogeneity which is associated with a poor prognosis and
resistance to therapy. The recent application of single-cell RNA-sequencing to tumor biology has shed further
light on the composition and dynamics of intra-tumor heterogeneity. The Yanai & Wong labs and many others
have provided evidence that such heterogeneity is not exclusively explained by genetic causes, but rather also
through the process of cellular plasticity. Emerging evidence also points to a crucial role for cellular plasticity in
the process of drug resistance. In non-small cell lung cancer (NSCLC), tumors treated with a KRASG12C inhibitor
have been shown to adapt by undergoing an adeno-to-squamous transition (AST). While this line of evidence
supports a major role for cellular plasticity in tumor adaptation to treatments, we lack an understanding of the
determinants, dynamics and strategies for preventing cell state transitions. In this proposal we seek to determine
the molecular programs that maintain the chromatin landscape using cutting-edge multi-omic approaches
coupled with clinically-relevant NSCLC murine models and their derivative organoids. In Aim 1 we propose a
systematic study of the adeno-to-squamous plasticity seeking to identify and delineate its chromatin-mediated
mechanisms. Our approach seeks to identify and test means for restricting the ability of cancer cells to undergo
AST. We first determine the dynamics of chromatin landscape changes during AST in murine-derived LUAD
organoids. Then we will map functional vulnerabilities along AST using a Perturb-Seq approach, and finally, we
will test for the potency of restricting AST with small molecule inhibitors against chromatin modifiers. In Aim 2,
we propose to predict the dynamics of cellular adaptation to context-specific targeted therapies used to treat
NSCLC. We will further seek to apply these predictions to primary tumor samples and correlate with clinical
outcomes with the goal of predicting the adaptive process. Overall, the impact of this work will be to provide
insights into cellular plasticity in lung cancer in clinically-relevant settings, and the identification of strategies for
synergistic treatment combinations to inhibit cell-state transitions and to eliminate the emergence of aggressive
subpopulations.

## Key facts

- **NIH application ID:** 10990251
- **Project number:** 1F99CA294252-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Ayushi Patel
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,550
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990251

## Citation

> US National Institutes of Health, RePORTER application 10990251, Resolving epigenetic determinants of cellular plasticity programs in non-small cell lung cancer (1F99CA294252-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10990251. Licensed CC0.

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