# Mechanisms of tumorigenesis in Brg1 mutant lung cancer

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $654,799

## Abstract

Summary/Abstract
Lung cancer is the leading cause of cancer-related deaths both worldwide and in the United States. It is also
one of the most genetically complex diseases – the two major subtypes of non-small cell lung cancer (NSCLC),
which are lung squamous cell carcinoma and lung adenocarcinoma rank 2nd and 3rd for the most mutations per
megabase of DNA in a study of 21 different tumor types. Efforts to map these mutations to genetic regions
have demonstrated that mutations in the BRG1-Associated Factor (BAF) complex, also known as the
mammalian SWI/SNF complex, are common. Inactivating mutations in BRG1, which encodes the ATPase and
helicase of the BAF complex, are present in 8-20% of NSCLCs. BRG1 (also known as SMARCA4) is often co-
mutated with KRAS, and there are no targeted therapies for this genetic subtype of lung cancer. The BAF
complex has long been known to be the epigenetic antagonist of the EZH2-containing Polycomb Repressive
Complex 2 (PRC2), but exactly how these complexes interact in the cancer setting is not well understood.
Recently, we demonstrated that EZH2 inhibitors synergize well with Topoisomerase II (TopoII) inhibitors such
as etoposide in BRG1 mutant NSCLCs. Our data suggest that a key role for BRG1 in lung cancer cells
involves facilitating TopoII complex function. Furthermore, our data suggest that combination of EZH2 inhibition
and TopoII inhibition uncovers the vulnerabilities of BRG1 mutant tumor cells to DNA repair defects. In order to
understand the mechanistic basis of the interactions between EZH2, BRG1 and TopoII, we propose to use a
panel of human and mouse isogenic models in which the only difference is the presence or absence of BRG1.
In Aim 1 we will identify mechanisms of DNA repair defects that occur with BRG1 deficiency in isogenic murine
and human lung cancer cell lines by assessing markers of double strand break repair mechanisms, non-
homologous end joining (NHEJ) and homologous recombination (HR). We will also determine if defects in DNA
repair cause the sensitivity of BRG1 mutant lung tumors to dual EZH2i/etoposide treatment. In Aim 2 we will
use mouse models to examine the preclinical effects of combination of EZH2 inhibition and etoposide against
BRG1-null lung tumors. Genetically engineered mice and patient derived xenograft (PDX) models will be used
to determine if the combination of EZH2 and TopoII inhibition is superior to standard of care therapies in place
for BRG1-mutant lung cancers. In Aim 3 we will characterize the immune microenvironment of BRG1-deficient
tumors and we will assess the impact of EZH2 inhibition with etoposide treatment on tumor immune cells. The
potential impact of these studies is large because BRG1 is one of the most commonly mutated genes in
NSCLC and there is currently no targeted therapy for this genetic subtype. In addition, EZH2 inhibitors have
moved to Phase I trials for other tumor types, and the combination of EZH2 inhibition and orally bioavailable
etoposide...

## Key facts

- **NIH application ID:** 9937670
- **Project number:** 5R01CA216188-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Carla F. Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $654,799
- **Award type:** 5
- **Project period:** 2018-06-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937670

## Citation

> US National Institutes of Health, RePORTER application 9937670, Mechanisms of tumorigenesis in Brg1 mutant lung cancer (5R01CA216188-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9937670. Licensed CC0.

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