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.
Highlights
Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets
We show that Bromodomain-containing protein 4 (BRD4) inhibition together with p53 activation results in enhanced anti-leukemia activity both in vitro and in vivo, in AML retaining wild-type TP53, compared to either inhibition alone
Apparent synergy depends on wild-type TP53, is linked to enhanced activation of p53 by bromodomain and extraterminal (BET) inhibitors (BETi) and depends on the expression of at least some p53 target genes, namely BBC3 and NOXA
Summary
Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. 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 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. In addition to disease heterogeneity between patients, marked sub-clonal heterogeneity has been observed within individual AML patients[4] To date these disease features have posed a significant obstacle to finding novel targeted agents with a broad therapeutic reach. Other combination strategies have demonstrated the utility of targeting wild-type p53 in AML11
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