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

Cancer research (2019-03-17)
Tatiana Shorstova, Maud Marques, Jie Su, Jake Johnston, Claudia L Kleinman, Nancy Hamel, Sidong Huang, Moulay A Alaoui-Jamali, William D Foulkes, Michael Witcher
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, ascites fluid
Sigma-Aldrich
GenElute Mammalian Total RNA Miniprep Kit, sufficient for 350 purifications
Sigma-Aldrich
GSK343, ≥98% (HPLC)
Sigma-Aldrich
Anti-RNA polymerase II subunit B1 (phospho CTD Ser-2) Antibody, clone 3E10, clone 3E10, from rat