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

Abstract

SummaryAcute 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 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.

metascreen: A modular tool for the design and analysis of drug combination screens

“…Additional combinations of targeted therapy and, more recently, with immunotherapy have been identified that can overcome resistance (Luke et al ., 2017). Similar effects have been observed for a wide variety of cancers, including AML, lung cancer and breast cancer (Fisusi and Akala, 2019; Latif et al ., 2021; Yuan et al ., 2019), and combination treatment clearly has the potential to significantly improve survival rates for cancer patients. However, given the sheer number of targeted therapies, identifying synergistic drug combinations is a major challenge, and several obstacles still need to be overcome.…”

Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance

“…A majority of AML cases contain wild-type TP53, and only 8% of de novo AML cases contain TP53 mutations according to TCGA. However, p53 is often rendered functionally deficient by over-expression of MDM2 (Latif et al, 2021). Selinexor blocks nuclear export and traps both proteins in the nucleus, thus hindering the MDM2-dependent shuttling of MDM2-p53 targeted for cytoplasmic degradation and hence induces transcriptional upregulation through phosphorylation of these sites (O'Keefe et al, 2003).…”

Degradation and inhibition of epigenetic regulatory protein BRD4 exacerbate Alzheimer’s disease-related neuropathology in cell models

“…The pathways/genes by which BRD4 affects BACE1 and APP processing in our AD model cells may associate with BRD4-related cell cycle and proliferation (CDKN1B, NRF2) or autophagy (18,51,52), which warrants future studies. Interestingly, using an oxidative stress-dependent activity, BRD4 binds and regulates the transcriptional factors p53 and SP1 (53,54), which have been related to the transcription of APP and BACE1 in AD (55,56). These results showed complex circuits for the regulatory role of BRD4 in transcriptional gene regulation.…”