BET protein degradation triggers DR5-mediated immunogenic cell death to suppress colorectal cancer and potentiate immune checkpoint blockade

Abstract

Bromodomain and Extra-Terminal domain (BET) family proteins are epigenetic readers thatplay a critical role in oncogenesis by controlling the expression of oncogenes such as c-Myc.Targeting BET family proteins has recently emerged as a promising anticancer strategy. However,the molecular mechanisms by which cancer cells respond to BET inhibition are not wellunderstood. In this study, we found that inducing the degradation of BET proteins by theProteolysis Targeting Chimeras (PROTAC) approach potently suppressed the growth of colorectalcancer (CRC) including patient-derived tumors. Mechanistically, BET degradationtranscriptionally activates Death Receptor 5 (DR5) to trigger immunogenic cell death (ICD) in CRCcells. Enhanced DR5 induction further sensitizes CRC cells with a mutation in Speckle-type POZprotein (SPOP). Furthermore, DR5 is indispensable for a striking antitumor effect of combiningBET degradation and anti-PD-1 antibody, which was well tolerated in mice and almost eradicatedsyngeneic tumors. Our results demonstrate that BET degradation triggers DR5-mediated ICD topotently suppress CRC and potentiate immune checkpoint blockade. These results provide arationale, mechanistic insights, and potential biomarkers for developing a precision CRC therapy byinducing BET protein degradation.