A germline SNP in BRMS1 predisposes patients with lung adenocarcinoma to metastasis and can be ameliorated by targeting c-fos Journal Article


Authors: Liu, Y.; Chudgar, N.; Mastrogiacomo, B.; He, D.; Lankadasari, M. B.; Bapat, S.; Jones, G. D.; Sanchez-Vega, F.; Tan, K. S.; Schultz, N.; Mukherjee, S.; Offit, K.; Bao, Y.; Bott, M. J.; Rekhtman, N.; Adusumilli, P. S.; Li, B. T.; Mayo, M. W.; Jones, D. R.
Article Title: A germline SNP in BRMS1 predisposes patients with lung adenocarcinoma to metastasis and can be ameliorated by targeting c-fos
Abstract: About 50% of patients with early-stage, surgically resected lung cancer will develop distant metastasis. There remains an unmet need to identify patients likely to develop recurrence and to design innovative therapies to decrease this risk. Two primary isoforms of BRMS1, v1 and v2, are present in humans. Using next-generation sequencing of BRMS1 on matched human noncancerous lung tissue and non-small cell lung cancer (NSCLC) specimens, we identified single-nucleotide polymorphism (SNP) rs1052566 that results in an A273V mutation of BRMS1v2. This SNP is homozygous (BRMS1v2A273V/A273V) in 8% of the population and correlates with aggressive biology in lung adenocarcinoma (LUAD). 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. BRMS1v2 A273V increases cell invasion in vitro and increases metastases in both tail-vein injection xenografts and LUAD patient-derived organoid (PDO) intracardiac injection metastasis in vivo models. Moreover, we show that BRMS1v2 A273V fails to interact with nuclear Src, thereby activating intratumoral c-fos in vitro. Higher c-fos results in up-regulation of CEACAM6, which drives metastases in vitro and in vivo. Using both xenograft and PDO metastasis models, we repurposed T5224 for treatment, a c-fos pharmacologic inhibitor investigated in clinical trials for arthritis, and observed suppression of metastases in BRMS1v2A273V/A273V LUAD in mice. Collectively, we elucidate the mechanism of BRMS1v2A273V/A273V-induced metastases and offer a putative therapeutic strategy for patients with LUAD who have this germline alteration. © 2022 The Authors.
Keywords: genetics; cell proliferation; mouse; animal; metabolism; animals; mice; germ cell; carcinoma, non-small-cell lung; lung neoplasms; cell motion; pathology; cell line, tumor; lung tumor; gene expression regulation; germ cells; gene expression regulation, neoplastic; lung adenocarcinoma; tumor cell line; cell movement; repressor protein; repressor proteins; nucleotide; non small cell lung cancer; nucleotides; adenocarcinoma of lung; humans; human; brms1 protein, human
Journal Title: Science Translational Medicine
Volume: 14
Issue: 665
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2022-10-05
Start Page: eabo1050
Language: English
DOI: 10.1126/scitranslmed.abo1050
PUBMED: 36197962
PROVIDER: scopus
PMCID: PMC9926934
DOI/URL:
Notes: Article -- Export Date: 1 November 2022 -- Source: Scopus
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MSK Authors
  1. Natasha Rekhtman
    425 Rekhtman
  2. Kenneth Offit
    789 Offit
  3. Matthew Bott
    135 Bott
  4. Nikolaus D Schultz
    487 Schultz
  5. David Randolph Jones
    417 Jones
  6. Yuan Liu
    22 Liu
  7. Neel Pankaj Chudgar
    15 Chudgar
  8. Kay See   Tan
    241 Tan
  9. Bob Tingkan Li
    278 Li
  10. Gregory Jones
    22 Jones
  11. Di He
    4 He
  12. Samhita Bapat
    3 Bapat