BET inhibitors potentiate chemotherapy and killing of SPOP-mutant colon cancer cells via induction of DR5

Bromodomain and extra-terminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that Death Receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer (CRC) cells. Induction of DR5 following BET inhibition was mediated by endoplasmic reticulum (ER) stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in CRC cells containing a mutation in Speckle-type POZ protein (SPOP), a subunit of BRD4 E3 ubiquitin ligase. In a CRC xenograft model, BETi combined with chemotherapy suppressed tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft (PDX) tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against CRC due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved CRC combination therapies.

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