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SWI/SNF-Compromised Cancers Are Susceptible to Bromodomain Inhibitors

Tatiana Shorstova1, Maud Marques1, Jie Su1

  • 1Departments of Oncology and Experimental Medicine, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada.

Cancer Research
|March 17, 2019
PubMed

Insights

Loss of SMARCA4/A2 predicts sensitivity to bromodomain and extraterminal motif protein inhibitors (BETi) in aggressive ovarian and lung cancers. These findings identify potential biomarkers for BET inhibitor therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Bromodomain and extraterminal motif protein inhibitors (BETi) show antitumor activity but lack predictive biomarkers for patient stratification.
  • SWI/SNF chromatin remodeling complexes, including SMARCA4 and SMARCA2, are crucial in cancer development.

Purpose of the Study:

  • To investigate the therapeutic potential of BET inhibitors in aggressive cancers lacking SMARCA4 and SMARCA2.
  • To identify predictive biomarkers for response to BET inhibitors.

Main Methods:

  • In vitro and in vivo antiproliferative assays using ovarian and lung cancer models.
  • Genetic manipulation (restoration and knockdown) of SMARCA4 and SMARCA2.
  • Transcriptomic analysis to identify molecular pathways affected by BET inhibitors.

Main Results:

  • Low-dose BET inhibitors demonstrated significant antiproliferative effects in SMARCA4/A2-deficient cancer models.
  • Restoration of SMARCA4/A2 conferred resistance to BET inhibitors, while knockdown sensitized resistant cells.
  • BET inhibitors downregulated receptor tyrosine kinase (RTK) signaling, including HER3, in deficient cells, which determined response.

Conclusions:

  • Loss of SMARCA4/A2 identifies tumors hypersensitive to BET inhibitors.
  • BET inhibitors represent a rational therapeutic strategy for poor-prognosis SMARCA4/A2-deficient cancers.
  • SMARCA4/A2 deficiency serves as a predictive biomarker for BET inhibitor efficacy.

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