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Cancer Res. 2019 May 15;79(10):2761-2774. doi: 10.1158/0008-5472.CAN-18-1545. Epub 2019 Mar 15.

SWI/SNF-Compromised Cancers Are Susceptible to Bromodomain Inhibitors.

Author information

1
Departments of Oncology and Experimental Medicine, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada.
2
Department of Human Genetics, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada.
3
Departments of Oncology and Human Genetics, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada.
4
Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.
5
Departments of Oncology and Human Genetics, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada michael.witcher@mcgill.ca william.foulkes@mcgill.ca.
6
Departments of Oncology and Experimental Medicine, McGill University, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada. michael.witcher@mcgill.ca william.foulkes@mcgill.ca.
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Contributed equally

Abstract

The antitumor activity of bromodomain and extraterminal motif protein inhibitors (BETi) has been demonstrated across numerous types of cancer. As such, these inhibitors are currently undergoing widespread clinical evaluation. However, predictive biomarkers allowing the stratification of tumors into responders and nonresponders to BETi are lacking. Here, we showed significant antiproliferative effects of low dosage BETi in vitro and in vivo against aggressive ovarian and lung cancer models lacking SMARCA4 and SMARCA2, key components of SWI/SNF chromatin remodeling complexes. Restoration of SMARCA4 or SMARCA2 promoted resistance to BETi in these models and, conversely, knockdown of SMARCA4 sensitized resistant cells to BETi. Transcriptomic analysis revealed that exposure to BETi potently downregulated a network of genes involved in receptor tyrosine kinase (RTK) signaling in SMARCA4/A2-deficient cells, including the oncogenic RTK HER3. Repression of signaling downstream of HER3 was found to be an important determinant of response to BETi in SMARCA4/A2-deficient cells. Overall, we propose that BETi represent a rational therapeutic strategy in poor-prognosis, SMARCA4/A2-deficient cancers. SIGNIFICANCE: These findings address an unmet clinical need by identifying loss of SMARCA4/A2 as biomarkers of hypersensitivity to BETi.

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