BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML

Abstract

Inhibitors of the bromodomain and extraterminal domain family (BETi) offer a new approach to treat hematological malignancies, with leukemias containing mixed lineage leukemia rearrangements being especially sensitive due to a reliance on the regulation of transcription elongation. We explored the mechanism of action of BETi in cells expressing the t(8;21), and show that these compounds reduced the size of acute myeloid leukemia cells, triggered a rapid but reversible G0/G1 arrest, and with time, cause cell death. Meta‐analysis of PRO‐seq data identified ribosomal genes, which are regulated by MYC, were downregulated within 3 hours of addition of the BETi. This reduction of MYC regulated metabolic genes coincided with the loss of mitochondrial respiration and large reductions in the glycolytic rate. In addition, gene expression analysis showed that transcription of BCL2 was rapidly affected by BETi but this did not cause dramatic increases in cell death. Cell cycle arrest, lowered metabolic activity, and reduced BCL2 levels suggested that a second compound was needed to push these cells over the apoptotic threshold. Indeed, low doses of the BCL2 inhibitor, venetoclax, in combination with the BETi was a potent combination in t(8;21) containing cells. Thus, BET inhibitors that affect MYC and BCL2 expression should be considered for combination therapy with venetoclax.

Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

“…Interestingly, in BT474, phosphorylation of MAPK and AKT pathway members were also marked with low target scores despite increases in total proteins levels and corresponding high target scores of total protein expression in EGFR, AKT and MAPK pathway members, suggesting the existence of BRD4 inhibitors altering signaling processes downstream of EGFR/HER2 in BT474. Consistent with existing literature, our differential and statistical analyses of target scores suggest that BETis reduce cell cycle progression (24)(25) as indicated by low target scores in cell cycle pathways.…”

Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion

“…6C). Cells need to maintain their redox ratio to effectively perform their functions, and a decreased redox ratio has been associated with the accumulation of reactive oxygen species and functional impairment (20)(21)(22). In addition, a decreased NAD(P)H  m and an increased FAD  m indicate reduced binding activities for NAD(P)H and FAD (23).…”

Co-Operativity between MYC and BCL-2 Pro-Survival Proteins in Cancer

“…Indeed, a wide range of BETi have now been tested together with various BH3-mimetics, though most studies have focussed on Venetoclax where enhanced responses from combining the drugs have been seen in vitro and in vivo in many haematological malignancies including T cell lymphoma, CLL, T cell acute lymphoblastic leukaemia, and diffuse large B cell lymphoma [ 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 , 297 ], and some solid tumours such as small cell lung cancer [ 298 ]. The dual BCL-XL/BCL-2 inhibitor Navitoclax was also shown to synergise with BETi in small cell lung cancer, colorectal cancer, glioma and B-cell lymphomas [ 299 , 300 , 301 , 302 ], whilst BH3-mimetics targeting MCL-1 enhance BETi activity in AML and melanoma [ 292 , 303 ].…”

“…This primes cells to apoptosis, especially that induced by Venetoclax, which can displace any BIM bound to BCL-2 for activation of BAX and BAK [ 237 ]. Levels of BCL-2 are also generally decreased following BETi treatment [ 290 , 292 , 293 , 294 , 298 , 305 ], though notably, other pro-survival proteins including BCL-XL [ 292 , 298 ], MCL-1 [ 292 ] and BFL-1 [ 295 ] have been shown to be reduced in different cancer types, leading to a further reduction in the apoptotic threshold of the cell. In colorectal cancer cells, BETi treatment led to repression of MYC-driven expression of miR1271-5p, which in turn led to increased NOXA levels and inhibition of MCL-1, thereby enabling synergy with ABT-263.…”