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      SWI/SNF-Compromised Cancers Are Susceptible to Bromodomain Inhibitors

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          Abstract

          <p class="first" id="d11418427e171">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. </p>

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          Author and article information

          Contributors
          (View ORCID Profile)
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          Journal
          Cancer Research
          Cancer Res
          American Association for Cancer Research (AACR)
          0008-5472
          1538-7445
          May 15 2019
          May 15 2019
          May 15 2019
          March 15 2019
          : 79
          : 10
          : 2761-2774
          Article
          10.1158/0008-5472.CAN-18-1545
          30877105
          50f3d336-2d5a-4255-9cc2-d56b78cb8069
          © 2019
          History

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