| Literature DB >> 33431824 |
Anne-Louise Latif1, Ashley Newcombe1, Sha Li2, Kathryn Gilroy1, Neil A Robertson1, Xue Lei2, Helen J S Stewart3, John Cole1, Maria Terradas Terradas1, Loveena Rishi1, Lynn McGarry4, Claire McKeeve5, Claire Reid1, William Clark4, Joana Campos6, Kristina Kirschner1, Andrew Davis2, Jonathan Lopez1, Jun-Ichi Sakamaki4, Jennifer P Morton1,4, Kevin M Ryan4, Stephen W G Tait1, Sheela A Abraham6,7, Tessa Holyoake6, Brian Higgins8, Xu Huang6, Karen Blyth1,4, Mhairi Copland6, Timothy J T Chevassut3, Karen Keeshan6, Peter D Adams9,10.
Abstract
Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain wild-type TP53, encoding the pro-apoptotic tumor suppressor p53. MDM2 inhibitors (MDM2i), which activate wild-type p53, and BET inhibitors (BETi), targeting the BET-family co-activator BRD4, both show encouraging pre-clinical activity, but limited clinical activity as single agents. Here, we report enhanced toxicity of combined MDM2i and BETi towards AML cell lines, primary human blasts and mouse models, resulting from BETi's ability to evict an unexpected repressive form of BRD4 from p53 target genes, and hence potentiate MDM2i-induced p53 activation. These results indicate that wild-type TP53 and a transcriptional repressor function of BRD4 together represent a potential broad-spectrum synthetic therapeutic vulnerability for AML.Entities:
Mesh：
Substances：
Year: 2021 PMID： 33431824 PMCID： PMC7801601 DOI： 10.1038/s41467-020-20378-8
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919