3102 – A Synthetic Lethality Approach to Eradicate AML via Synergistic Activation of Pro-Apoptotic p53 By MDM2 and BET Inhibitors

Li, S. et al. (2020) 3102 – A Synthetic Lethality Approach to Eradicate AML via Synergistic Activation of Pro-Apoptotic p53 By MDM2 and BET Inhibitors. 49th Annual Scientific Meeting of the ISEH (International Society for Experimental Hematology), 19-21 Aug 2020. (doi: 10.1016/j.exphem.2020.09.115)

Abstract

Acute Myeloid Leukemia (AML) is a typically-lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, over 90% of AML patients retain wild type TP53, encoding pro-apoptotic tumor suppressor p53. However, wild-type p53 functions are frequently suppressed by MDM2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation. MDM2 inhibitors (MDM2i), which activate wild-type p53, show encouraging pre-clinical activity, but limited clinical activity. In an effort to find targets that synergize with p53 activation via MDM2i and minimize toxicity, we performed a cell-based synthetic lethal drug screen and a CRISPR viability screen. These screens identified BRD4 inhibition as a candidate synthetic lethal partner of MDM2i. BRD4 is a member of the Bromodomains and Extraterminal (BET) family of proteins, a transcriptional co-activator and already an AML therapeutic target. Surprisingly, we found inhibition of BRD4 alone induces expression of some of p53 target genes. We unexpectedly reveal that BRD4 binds to p53 target genes and acts as a transcriptional repressor of these genes. Synergistic cell killing by the drug combination depends on synergistic activation of p53 target genes, such as PUMA and NOXA, due to simultaneous stabilization of p53 by MDM2i and relief of BRD4-mediated repression by BETi (BET inhibitors). Our combined therapy of MDM2i and BETi is synergistically lethal to human AML cell lines harboring wild type TP53 in vitro, against two mouse models of AML in vivo, and against primary human patient blasts in vitro. Taken together, our data show BRD4 represses p53-mediated transcription activation and apoptosis in AML. Therefore, co-targeting wild-type TP53 and a transcriptional repressor function of BRD4 represent a novel synthetic lethal vulnerability in AML.

• Item Type: Conference or Workshop Item
• Additional Information: Conference abstract published in Experimental Hematology, Vol.88(Supplement):S70.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cole, Mr John
• Authors: Li, S., Latif, A.-L., Newcombe, A., Gilrory, K., Robertson, N., Finlay, D., Lei, X., Stewart, H., Barbosa, K., Cole, J., Terradas, M. T., Rishi, L., McGarry, L., McKeeve, C., Reid, C., Clark, W., Campos, J., Kirschner, K., Lopez, J., Sakamaki, J.-I., Morton, J., Ryan, K., Tait, S., Abraham, S., Holyoake, T., Higgins, B., Huang, X., Copland, M., Chevassut, T., Deshpande, A., Keeshan, K., and Adams, P.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• ISSN: 0301-472X