BRD4-mediated repression of p53 is a target for combination therapy in AML

Latif, A.-L.; Newcombe, A.; Li, S.; Gilroy, K.; Robertson, N.; Lei, X.; Stewart, H.; Cole, J.; Terradas, M. T.; Rishi, L.; McGarry, L.; McKeeve, C.; Reid, C.; Clark, W.; Campos, J.; Kirschner, K.; Davis, A. E.; Lopez, J.; Sakamaki, J.-I.; Morton, J.; Ryan, K. M.; Tait, S.; Abraham, S.; Holyoake, T.; Higgens, B.; Huang, X.; Blyth, K.; Copland, M.; Chevassut, T.; Keeshan, K.; Adams, P. D.

doi:10.1101/2020.09.16.291930

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bioRxiv · 10.1101/2020.09.16.291930

BRD4-mediated repression of p53 is a target for combination therapy in AML

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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 synergistic toxicity of combined MDM2i and BETi towards AML cell lines, primary human blasts and mouse models, resulting from BETis 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.

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Latif, A.-L., Newcombe, A., Li, S., Gilroy, K., Robertson, N., Lei, X., Stewart, H., Cole, J., Terradas, M. T., Rishi, L., McGarry, L., McKeeve, C., Reid, C., Clark, W., Campos, J., Kirschner, K., Davis, A. E., Lopez, J., Sakamaki, J.-I., Morton, J., Ryan, K. M., Tait, S., Abraham, S., Holyoake, T., Higgens, B., Huang, X., Blyth, K., Copland, M., Chevassut, T., Keeshan, K., Adams, P. D.. 2020-09-16. BRD4-mediated repression of p53 is a target for combination therapy in AML. https://doi.org/10.1101/2020.09.16.291930

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