# Targeting SNP BRMS1v2 A273V/A273V to reduce metastases in lung adenocarcinoma

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $474,928

## Abstract

PROJECT SUMMARY/ABSTRACT
Metastatic lung cancer kills 160,000 people in the United States annually. In patients with early stage,
surgically resected lung cancer 10-60% will develop recurrence and distant metastasis. There is an unmet
need to predict the likelihood for developing distant metastases and for innovative adjuvant therapies that
could decrease this risk. Our group has shown that the metastasis suppressor gene, Breast Cancer Metastasis
Suppressor 1 (BRMS1), inhibits metastases in lung adenocarcinoma (LUAD). Two primary isoforms of
BRMS1, v1 and v2 are present in humans. Next generation sequencing of BRMS1 reveals a single nucleotide
polymorphism (SNP) rs1052566 (G>A) that causes an A273V mutation of BRMS1v2. The homozygous A allele
(BRMS1v2A273V/A273V) is present in 8% of LUAD patients and correlates with a poor progression-free survival of
patients with stage I-II, node-negative LUAD in the TCGA cohort (N=278). Mechanistically we show that
BRMS1v2 A273V abolishes the metastasis suppressor function of BRMS1v2 and promotes robust cell invasion
and metastases by activation of c-fos-mediated gene-specific transcriptional regulation. Specifically, BRMS1v2
A273V increases cell invasion in vitro and increased metastases in both tail-vein injection xenograft and LUAD
patient-derived organoid (PDO) intracardiac injection metastasis in vivo models. Moreover, we show that
BRMS1v2 A273V fails to interact with Src, resulting in c-fos activation and increased L1CAM. Inhibition of c-fos
or knockdown of L1CAM reduces BRMS1v2 A273V-promoted cell invasion. Our overarching goals are 1) to
clarify the contribution of the c-fos in BRMS1v2A273V/A273V LUAD metastases, and 2) to assess the efficacy of
targeting BRMS1v2A273V/A273V to reduce metastases and improve survival. Two Specific Aims will test our
hypotheses: Aim 1) Investigate the mechanisms through which BRMS1v2 A273V promotes LUAD metastasis.
We will perform RNA-seq in our BRMS1v2WT/WT and isogenic BRMS1A273V/A273V cells followed with an in vivo
CRISPR/sgRNAs screen to identify functional BRMS1v2 A273V downstream target genes and the requirement
of c-fos. Next, we will express different forms of nuclear Src in LUAD cells to assess the role of nuclear Src/c-
fos pathway in BRMS1v2 A273V-mediated gene-specific transcriptional regulation. Aim 2) Understand the
significance of BRMS1v2A273V/A273V in promoting LUAD metastasis. We will assess the ability of
BRMS1v2A273V/A273V to predict metastases by leveraging our extensive, clinically-annotated biorepository of 893
stage I-II (node-negative) human LUAD specimens. We then will use our newly developed PDO model to
examine 1) the therapeutic significance of targeting c-fos in metastasis suppression of BRMS1v2A273V/A273V
LUAD by repurposing the c-Fos inhibitor T5224, and 2) the dominant form of BRMS1 that governs metastases.
Impact: Our work will provide mechanistic and translational evidence to highlight BRMS1v2A273V/A273V as an
important germline marker to...

## Key facts

- **NIH application ID:** 10460260
- **Project number:** 5R01CA240472-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** David R Jones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $474,928
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460260

## Citation

> US National Institutes of Health, RePORTER application 10460260, Targeting SNP BRMS1v2 A273V/A273V to reduce metastases in lung adenocarcinoma (5R01CA240472-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10460260. Licensed CC0.

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