# Drivers of histologic transformation in EGFR-mutant lung cancer

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $396,790

## Abstract

Project Summary:
EGFR-mutant lung cancers (LCs) are initially highly responsive to EGFR inhibitors, but cancer adaptation
resulting in drug resistance universally occurs. Acquired resistance mediated by lineage plasticity is particularly
problematic; EGFR-mutant lung adenocarcinomas (ACs) can transform into either small cell (SC) or squamous
cell (SQ) lung cancers. Understanding the molecular determinants of histologic transformation is critical to inform
therapeutic strategies to block the emergence of new cell lineage states induced by cancer treatments. We have
established that concurrent alterations in TP53 and RB1 are necessary but not sufficient to induce SC
transformation in EGFR-mutant LCs; EGFR/TP53/RB1-mutant LCs have a 25% likelihood of transformation over
time. In addition, we have assembled a cohort of resected mixed histology tumors (AC/SC and AC/SQ) that
serve as a model of transformation where microdissection by histology isolates paired tumors representing pre-
and post- transformation states. Using these complementary systems directly derived from patients, we will
perform a mechanistic analysis of lineage plasticity utilizing EGFR/TP53/RB1-mutant LCs at high risk for
transformation and mixed histology tumors that represent transformation in progress.
Our central hypothesis is that while the somatic mutational landscape is critical in establishing conditions
permissive of lineage plasticity, actual transformation to an alternative lineage is predominantly epigenetically
driven and associated with consistent globally altered patterns of gene expression. Our first aim is to
comprehensively molecularly characterize lineage plasticity using parallel whole exome, RNA and bisulfite
sequencing focusing on patient samples from before, during (mixed AC/SC and AC/SQ) and after transformation.
Resected mixed histology tumors (AC/SQ) will be microdissected and molecularly characterized as paired
tumors. The second aim of the proposal is to investigate subclonal dynamics contributing to lineage plasticity
using single cell RNA-sequencing. We will interrogate serial samples from our ongoing clinical trial to prevent
transformation in patients with EGFR/TP53/RB1-mutant lung ACs and resected mixed histology AC/SC and
AC/SQ tumors. Finally, we will utilize our patient-derived xenograft models of transformation to genetically and
pharmacologically assess putative drivers of transformation, exploring rational interventional strategies. Our
preliminary work has proposed initial targets (Wnt, EZH2, AKT, NOTCH) that will be expanded with findings from
this proposal. Novel therapeutic interventions will be proposed based on our findings that can be rapidly
translated to the clinical setting for LC and other disease states characterized by lineage plasticity.

## Key facts

- **NIH application ID:** 10492044
- **Project number:** 5R01CA264078-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Charles M. Rudin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $396,790
- **Award type:** 5
- **Project period:** 2021-09-21 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492044

## Citation

> US National Institutes of Health, RePORTER application 10492044, Drivers of histologic transformation in EGFR-mutant lung cancer (5R01CA264078-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10492044. Licensed CC0.

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