Authors:

Juliette Jacques

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Bromodomain and extra-terminal (BET) proteins are a family of four members: BRD2, BRD3, BRD4, and BRDT. These proteins function as epigenetic readers, binding to acetylated lysine residues on histones. BET proteins are often dysregulated and drive oncogene transcription across various cancers. Given their critical role in transcriptional regulation, they have emerged as promising therapeutic targets for small-molecule BET inhibitors, including JQ1. Despite promising preclinical results and ongoing BET inhibitor clinical trials, their therapeutic efficacy has been hindered by developed resistance. However, the mechanisms underlying this resistance remain poorly understood. Our RNA- seq analysis revealed significant upregulation of BRD2 upon JQ1 treatment in pancreatic ductal adenocarcinoma (PDAC) cell lines, suggesting BRD2 may mediate adaptive resistance to BET inhibition across cancer types. Functional studies confirmed that BRD2 depletion sensitizes PDAC cells to JQ1 in vitro and in vivo. Additionally, upregulation of BRD2 upon JQ1 treatment was observed in leukemia, glioblastoma, lung, and breast cancer. This suggests that BRD2 upregulation plays a conserved role in resistance mechanisms, potentially conferring a survival advantage to cancer cells. These results highlight BRD2 as a key factor in BET inhibitor resistance and inform the development of strategies to enhance the clinical impact of BET inhibitors in cancer therapeutics. Calmodulin-Dependent Kinase II Regulation by Methylation - Role of the R9 Site Ryan Jain

Source:

UC Davis / Microbiology & Molec Genetics / 2025

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Co-authors:

Juliette Jacques