Nat Commun:BRD4 mediated p53 inhibition is a joint therapeutic target for acute myeloid leukemia

Acute myeloid leukemia (AML) is a typical deadly molecular heterogeneous disease that currently has few broad-spectrum therapeutic targets for the disease.
although there has been some progress in molecular biology of AML, improving clinical outcomes in patients is still urgent.
2019, the five-year survival rate for patients diagnosed with AML is still less than 30%.
AML, as a genetic and presumed genetic heterogeneous disease, is characterized by the recurrence of the disease and the diversity of chromosomal structure and the genetic mutations associated with different functional subtypes.
in addition to disease heterogeneity between patients, significant subclonal heterogeneity was observed in individual AML patients.
these disease characteristics have also become a major obstacle to the search for new broad-spectrum targeted drugs.
previous studies have shown that most AML retains the wild type of TP53, which encodes the apoptosis tumor inhibitor p53.
MDM2 inhibitors (MDM2i), which activate wild p53, and BET inhibitors (BETi), which target the BET family co-activation factor BRD4, both showed positive preclinical activity, but their clinical activity as a single drug was limited.
MDM2 and BET inhibitors combined to enhance the killing of wild TP53 to AML cells Since both drugs can in principle target a wide range of AML molecular subsypes, and both have different effects, the study aims to explore the effects of the combined use of MDM2i and BETi.
the study, researchers found that in AML cell line, primary osteoblasts, and mouse models, the combined use of MDM2i and BETi had a better toxicity-enhancing effect than a single drug.
further mechanism studies have also confirmed how this effective combination of drugs co-induces apoptosis-promoting p53 target genes.
BETi is able to remove the inhibitory form of BRD4 from the p53 target gene, thereby enhancing MDM2i-induced p53 activity.
in mouse models, MDM2 and BET inhibitors co-removed AML, the results showed that wild TP53 and BRD4, transcription inhibitors, could be potential broad-spectrum synthetic therapeutic targets for AML.