# BRMS1-mediated suppression of metastases in p53 mutant lung adenocarcinoma

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $559,847

## Abstract

Metastatic lung cancer kills >180,000 people in the United States annually and only ~10% of patients with lung
adenocarcinoma (LUAD) have targetable driver genomic alterations. There remains an unmet need for
innovative therapies. BRMS1 is a metastasis suppressor gene that is decreased in LUAD and is associated
with increased cancer migration, invasion, and poor prognosis. Mutations in DNA binding domain (DBD) of p53
are common in LUAD and are associated with increased metastases. We have made a novel observation
that BRMS1 functions as transcription factor for selected metastasis-related genes in p53mut but not
p53WT LUAD. Specifically, we show that BRMS1 binds promoter regions containing active p53 responsive
elements to transcriptionally regulate metastasis-related genes, Maspin and Serpine1, in p53mut but not p53WT
LUAD. Moreover, we demonstrate that BRMS1 expression is related to biologically distinct histologic subtypes
of LUAD and that restoration of BRMS1 using the CK2 inhibitor CX4945 results in significantly less cell
migration and invasion in p53mut compared with p53WT LUAD. Our overarching goal is to determine the
importance of maintaining BRMS1 in the context of p53 mutations using clinically relevant, human LUAD
samples, patient-derived organoids (PDO), and conditional GEMM models. Two Specific Aims will test our
hypotheses: Aim 1) Identify downstream targets and associated components of BRMS1-mediated transcription
in p53mut LUAD. We will use ChIP-seq to identify genome-wide specific BRMS1-DNA binding regions in p53mut
LUAD cells. We will then determine the functional significance of BRMS1-DNA binding on transcriptional
regulation by performing RNA-seq in BRMS1WT and BRMS1KO LUAD isogenic cells with different p53 status.
Next, using shRNA screens combined with reporter gene assays to characterize gene-specific components,
we test the hypothesis that BRMS1 differentially regulates transcription via interaction with unique transcription
co-factors in p53mut LUAD. Aim 2) Determine the requirement for BRMS1 in regulating metastases in human
p53mut LUAD. We will leverage our extensive, clinically-annotated biorepository of >2000 human LUAD
specimens with varying p53 mutational profiles, pathologic stages, and histologic subtypes to characterize the
spectrum of LUAD tumors. We then examine the efficacy of the CK2 inhibitor, CX4945, in preventing BRMS1
degradation and decreasing metastases in specific histological subtypes of LUAD using our newly developed
LUAD patient-derived organoid (PDO) model of metastases. We use this PDO model modified with an
inducible expression system to assess the importance of maspin, and serpine1 on BRMS1-mediated
metastasis suppression. Finally, using our newly created Brms1-/-/KrasG12D GEMM with intratracheal delivery of
p53mut CRISPR we create a metastatic LUAD mouse model to assess the requirement of BRMS1 for CX4945-
mediated suppression of metastases. Impact: Our work will provide mechanistic and transl...

## Key facts

- **NIH application ID:** 9829088
- **Project number:** 5R01CA217169-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** David R Jones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $559,847
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829088

## Citation

> US National Institutes of Health, RePORTER application 9829088, BRMS1-mediated suppression of metastases in p53 mutant lung adenocarcinoma (5R01CA217169-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9829088. Licensed CC0.

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