# Mechanisms and Vulnerabilities of  SWI/SNF chromatin remodeling complex mutant lung cancer

> **NIH NIH R37** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $448,439

## Abstract

Project Summary
 Lung cancer is a devastating disease that remains the top cause of cancer mortality. Despite recent
advances, the majority of patients with lung cancer lack effective therapeutic options, underscoring the dire need
for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the
SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a
frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung
cancer. We recently demonstrated that Smarca4 acts as a bona fide tumor suppressor in mice and cooperates
with p53 loss and Kras activation. Importantly, SMARCA4 mutant cancer cells have heightened sensitivity to
inhibition of oxidative phosphorylation (OXPHOS) by a novel small molecule, IACS-10759. Mechanistically, we
showed that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a
therapeutically relevant vulnerability.
 Taking these observations together, we hypothesize that OXPHOS inhibition using IACS-10759 is an
attractive therapeutic strategy for lung cancers with mutations in the SWI/SNF complex. The major objectives of
the proposed study are to discover the mechanistic basis of the metabolic rewiring in SWI/SNF mutants and
provide preclinical evidence to guide future clinical study of IACS-10759 in patients with SWI/SNF mutant lung
cancer. Due to the unique microenvironment of lung cancer including high local oxygen tension, it is imperative
to study therapeutic agents targeting metabolism orthotopically. Hence, we will test efficacy of IACS-10759 in
GEM models of lung cancer. Further, PDX models have emerged as powerful tools to help guide treatment
strategies. Thus, we propose to determine the potential of OXPHOS inhibition in various SWI/SNF mutant PDX
model systems. While our preliminary data indicates that IACS-10759 treatment leads to tumor growth inhibition,
synergistic combination strategies are expected to be even superior in efficacy. Thus, we propose to identify
optimal combination agents that synergize with IACS-10759 by using a chemo-genetic screen. Here, we will use
CRISPR-Cas9 and a custom designed library of guide RNAs against genes targeted by FDA approved drugs
(FDAome). We will validate the results of the screen by performing one-on-one drug combination studies in vivo.
Finally, our preliminary data suggests that SMARCA2 is required for expression of PGC1α, a master
transcriptional regulator of mitochondrial biogenesis and OXPHOS, in SMARCA4 mutant cells. We know from
our published work that PGC1α is essential in SMARCA4 deficient cells. Thus we hypothesize that SMARCA2
is a survival factor and a major driver of metabolic rewiring in SMARCA4 deficient cells in a PGC1α dependent
manner. In conclusion, our study is expected to provide mechanistic insight into the metabolic dysregulation of
SWI/SNF mutant lung cancers and lay the foundation for fut...

## Key facts

- **NIH application ID:** 10864047
- **Project number:** 5R37CA251629-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Yonathan Lissanu
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $448,439
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10864047

## Citation

> US National Institutes of Health, RePORTER application 10864047, Mechanisms and Vulnerabilities of  SWI/SNF chromatin remodeling complex mutant lung cancer (5R37CA251629-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10864047. Licensed CC0.

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