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Currently, most BETi target all the members of BET subfamily, including BRD2, BRD3, BRD4 and BRDT. Exogenous expression of each BET protein in distinct cell types, either alone or in combination, would help to elucidate tissue-specific oncogenic properties of these chromatin-binding proteins and allow their impact on sensitivity to BETi to be examined.
A key discovery regarding the anti-tumour activity of BETi is that these drugs, including first- and second-generation compounds, silence the expression of MYC in preclinical studies, and it appears that the amplification of MYC family members predicts sensitivity to BETi in multiple tumour types.
However, although MYC is commonly downregulated in cells exposed to BETi, it is not always clear that this event mediates the anti-proliferative effects of BETi, and several studies have shown that MYC does not always act as a mediator of BETi sensitivity.
It is possible that high concentrations of BETi used in preclinical studies have off-target effects that are either exacerbated in MYC-expressing cells, or act through BET-independent pathways to silence MYC.
Again, these concerns highlight the need to carry out preclinical studies at relevant concentrations, not far in excess of the IC50 required to dissociate BET proteins from chromatin. To establish MYC amplification as a robust predictive biomarker, clinical studies demonstrating significant patient responses in MYC -amplified patient cohorts, coupled with a downregulation of MYC in response to drug exposure, would be required.
Clinical data, described below, suggest that MYC suppression holds promise as a pharmacodynamic biomarker. Three types of biomarkers to BETi treatment exist: predictive biomarkers, biomarkers of resistance and pharmacodynamic biomarkers. Understanding mechanisms through which BRD4-driven transcriptional programmes are regulated is likely to reveal vulnerabilities that could be exploited using BETi.
BRD4 and another bromodomain protein, SMARCA4, independently but concurrently activate gene expression by simultaneously binding to different regulatory elements in their target genes. These findings demonstrate that the loss of SMARCA4 might act as a potential predictive biomarker for the effectiveness of BETi Fig.
BETi inhibitors act primarily through the repression of oncogenic networks, including those regulated by MYC protein levels. It should therefore not be surprising that in some cancers, such as AML and triple-negative breast cancer, epigenetic reprogramming to maintain the expression of these oncogenic networks is a mechanism of both intrinsic and acquired resistance.
Many types of cancer are characterised by increased transduction through these classical oncogenic networks. Notably, numerous studies found that BETi inactivate transcriptional programmes involved in RTK signalling exclusively in sensitive cells.
On nearly half of these active enhancers, an enrichment for BRD4 binding was concurrently observed. Notably, based on understanding this underlying mechanism of resistance, it was revealed that these neuroblastoma cell models were sensitive to PI3K inhibitors in combination with BETi.
Likewise, ovarian cancer cells acquiring BETi resistance through long-term culture reprogrammed their kinome to elevate signalling through PI3K and RAS pathways. However, exome sequencing was not carried out, so de novo activating mutations cannot be excluded. In colorectal cancer models, KRAS mutations do not appear to render tumour cells more resistant to BETi.
In KRAS -mutant-carrying NSCLC models, sensitivity to BETi was reported, but 2. mTOR is a key downstream effector of the PI3K pathway, regulating diverse processes including protein synthesis and cytoskeletal remodelling.
In this model, loss of LKB1 is expected to increase mTOR signalling thereby imparting resistance to BETi. Together, these data suggest that gain-of-function mutations and constitutive activity through the PI3K and RAS signalling axes might act as biomarkers of resistance to BETi in specific types of cancer Fig.
As described below, this information points towards the use of rational combination therapies to overcome this resistance. The stability of BET proteins might also influence their susceptibility to inhibitors. Remarkably, in endometrial cancer, some SPOP SRD mutations, such as RQ, lead to an enhanced association between SPOP and BET-family members, which results in increased ubiquitylation, decreased BET protein levels and enhanced sensitivity to BETi.
Overall, SPOP mutations hold great promise as biomarkers of both resistance and sensitivity to BETi. These studies reinforce the notion that BRD4 levels within tumours modulate the responsiveness to BETi.
The data also suggest that the activity of BET proteins might be regulated by proteasomal degradation across tissue types, which opens new therapeutic perspectives.
Especially relevant might be targeting BET proteins, either individually or combinatorially, using a proteolysis targeting chimera PROTAC, reviewed in ref. Pharmacodynamic biomarkers enable the clinical monitoring of drug activity in vivo, ideally using simple PCR or ELISA-based assays that act in lieu of more complex approaches to measure the accumulation of an administered drug within plasma or the tumour itself.
Identifying robust pharmacodynamic biomarkers for BETi in preclinical settings will undoubtedly facilitate the optimisation of their clinical utility.
Generating such biomarkers might be enhanced through the preclinical use of orthotopic xenografts that mimic a relevant tumour microenvironment, thereby more accurately predicting drug response in a time- and dose-dependent manner.
Upregulation of HEXIM1 has been identified as a potential pharmacodynamic biomarker in numerous tumour xenografts and whole blood samples in response to ABBV treatment Fig. A small clinical trial showed a trend for both MYC repression and an increase in HEXIM1 in the plasma of patients treated with the BETi BAY for mixed, refractory malignancies.
This is below administered drug levels eliciting dose-limiting toxicities. This may cast some doubt on the necessity for BETi to lower MYC transcription in order to provoke an anti-tumour response. Another preclinical study reported that MYC and HEXIM1 act most robustly as tumour-based pharmacodynamic biomarkers for BETi and that the corresponding mRNAs did not show optimal correlation with drug accumulation within blood samples.
The study from Yeh et al. This is especially relevant for CCR2, that is known to recruit myeloid-derived suppressor cells to the tumour niche, which in turn, promotes tumour growth. After extensive preclinical evaluation, but in the absence of robust predictive biomarkers, multiple clinical trials of BETi against solid and haematological types of cancer have been initiated.
To date, ~25 clinical trials are either ongoing or have been completed Table 2. With the exception of NMC, these trials are not targeting specific molecular subtypes, and this lack of biological rationale, plus unexpected toxicities, might limit clinical efficacy in the short term.
Strong results from the preclinical evaluation of BETi in multiple myeloma mled to elevated expectations for achieving clinical responses in this malignancy.
The first published clinical trials of BETi all used the widely studied drug OTX MK Among five patients with MYC-positive DLBCL, only one showed a favourable outcome to BETi exposure.
However, this dose might not be universally achievable because almost all of the patients in this trial displayed dose-limiting toxicities, including thrombocytopenia, anaemia, neutropenia, gastrointestinal events and fatigue.
Based on published clinical data, these toxicities appear to be common for this class of drugs regardless of the type of cancer being treated or the chemical structure of the BETi being tested.
Once maximum drug activity is identified in the plasma or intratumorally, higher doses are likely to elicit strong off-target effects. As described above, NMC is characterised by BRD4 fusions leading to aberrant BRD4 activity.
Again, based on preclinical data, expectations that BETi would show efficacy against these tumours were high and, consequently, the first published clinical trial using BETi was focused on NMC. Clinical responses were observed in two patients, but all four patients succumbed to their disease between 5 and 19 months post-diagnosis.
Complementing this study, Lewin et al. Partial responses have also been described for NMC patients treated with the I-BETA molibresib. In addition to MYC and BRD4—NUT-driven malignancies, BETi have been tested against several AMLs and diverse solid tumours. In an initial study of OTX in a cohort of 41 patients with AML, 59 three patients showed partial responses and two patients showed a complete response lasting 2—5 months.
Notably, however, an attempt to identify potential biomarkers including mutations in 42 genes failed to uncover any clear molecular pathologies among responders. Although published reports of the use of BETi against solid tumours have not met expectations, responses have been observed, again underscoring a need for predictive biomarkers.
Perhaps the most promising preclinical data against solid tumours beyond NMC have come from prostate cancer models. This study included patient cohorts harbouring both solid and haematological tumours. In total, 65 patients were enrolled, including those with NMC, small cell- and non-small lung cancer, triple-negative breast cancer TNBC , CRPC, colorectal cancer, neuroblastoma and multiple myeloma.
While complete responses were not reported, four NMC patients had confirmed and unconfirmed partial responses and one TNBC patient achieved unconfirmed partial response. Based on these data, we predict that BETi might play an important clinical role in the management of NMC.
However, it is clear that predictive biomarkers and, most likely, combinatorial approaches, will be essential moving forward and, perhaps more importantly, it will be critical to overcome in-class dose-limiting toxicities.
BET proteins are important for multiple cellular processes required for homoeostasis, which might explain why complete bromodomain inhibition leads to unexpected toxicities.
Advances in the medicinal chemistry of BETi might be required to dissociate anti-cancer effects from the inhibition of physiological pathways required for homoeostasis. The necessity of using such high doses to combat cancer proliferation strongly suggests a high level of intrinsic resistance to these compounds across tumour types that has not been widely studied or appreciated.
The precise mechanisms of intrinsic resistance to BETi remain unclear, but multiple studies suggest that the activation of oncogenic signalling pathways including those mediated by PI3K and RAS might be involved and that repression of these pathways might act as key mediators of BETi activity.
We suggest that, consequently, these pathways also play a role in intrinsic BETi resistance and could therefore be targeted in conjunction with the use of BETi. Several studies report the PI3K pathway as a determining factor influencing BETi both intrinsic and acquired resistance, and suggest that this resistance could be successfully overcome through the combination treatment using BETi and PI3K inhibitors.
As described below, a better understanding the mechanisms of resistance mediated by constitutive signalling through PI3K and MAPK pathways will probably reveal new therapeutic options for these patients. Multiple studies demonstrate that combining BETi with tyrosine kinase inhibitors effectively overcomes both intrinsic and acquired resistance to these drugs in several types of cancer.
A chemical combinatorial screening of JQ1 with around compounds aimed at finding effective small molecule combination therapies with BETi revealed PI3K inhibitors to be the most potent partners against neuroblastoma both in vitro and in animal models. Melanomas bearing NRAS mutations frequently have high BRD4 mRNA and protein expression levels, which are associated with a poor outcome.
The combined treatment downregulated proteins implicated in cell cycle regulation and apoptosis. Recent evidence indicates that cell cycle regulation resulting from the combination of BETi with MAPK inhibitors may stem from a broad repression of nucleotide metabolism in ovarian cancers.
Moving forward, it will be important to examine whether this mechanism is relevant to other cancer models sensitive to this combination. About half of all recurrent TNBC express high levels of n-MYC. It remains to be experimentally proven which, if any, of these correlates are responsible for the observed growth inhibition.
In PDX models of TNBC, intermediate or high levels of n-MYC predicted response to the synergistic combination of trametinib with either JQ1 or another BETi, INCB, whereas PDX models with low levels of n-MYC were more resistant.
As stated above, the half-life of JQ1 in vivo is quite short, and high doses are generally required to achieve effects. Additional combinations using BETi also show promise. KRAS mutations are very prevalent in pancreatic ductal adenocarcinoma PDAC and is associated with a very poor prognosis.
That being said, independent reports have supported the applicability of this combination in vivo, using either a MYC-driven lymphoma model or against a neuroblastoma model. As stated previously, BET proteins might act as oncogenes, at least in part, through the activation of genes involved in cell cycle progression.
As such, it would be logical to combine BETi with inhibitors of CDKs. This approach has been explored successfully in NMC. An interesting combination of BETi with vitamin C was demonstrated to be effective using both in vitro and in vivo TNBC models. In this study, simultaneous treatment resulted in a decrease in histone acetylation, perhaps consistent with the findings of efficacy between BETi and HDAC inhibitors.
This strategy of combining BETi with vitamin C not only in TNBC, but also in melanoma significantly improved the EC50 of BETi by reducing it to a nanomolar range. Even though responses differ across tissue types, the cell response to BETi is generally cytostatic in nature, resulting in delayed cell cycle progression.
Thus, it might be logical to complement this cytostatic response with promoters of an apoptotic response. Supporting this idea are a number of studies showing synergy between several BETi and the BCL-2 inhibitor venetoclax ABT against haematopoietic malignancies. The combination of inhibitors of poly-ADP ribose polymerase PARP with BETi has shown great promise, instigating a loss of proliferation across many cell types, including ovarian, breast and pancreatic cancer models both in vitro and in vivo.
The development of BETi has provided important insights into the key role of BET proteins in the transcriptional control of proto-oncogenes, and highlighted the potential of these proteins as therapeutic targets. Preclinical studies have demonstrated a remarkable anti-proliferative activity of BETi against tumours, including several incurable subtypes.
It is our opinion that a lack of biomarkers predicting sensitivity to BETi, coupled with the use of non-clinically relevant doses in preclinical studies, is limiting the application of these agents in clinical practice. Further research and mechanistic studies will help to identify such biomarkers, and the development of novel, highly selective bromodomain inhibitors will help prevent toxicities.
Finally, exciting new data indicate that, in the long term, BETi are likely to hold the most clinical potential as a part of combinatorial regimens.
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Natl Acad. USA , — Wu, X. Inhibition of BRD4 suppresses cell proliferation and induces apoptosis in renal cell carcinoma. Cell Physiol. Dawson, M. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.
Lu, L. Inhibition of BRD4 suppresses the malignancy of breast cancer cells via regulation of Snail. Cell Death Differ. Nicodeme, E. Suppression of inflammation by a synthetic histone mimic.
Dey, A. BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses. EMBO J. Belkina, A. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. Wienerroither, S.
Regulation of NO synthesis, local inflammation, and innate immunity to pathogens by BET family proteins. Baud, M. Chemical biology.
A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. Bardini, M. Cancer Ther. Mirguet, O. Discovery of epigenetic regulator I-BET lead optimization to afford a clinical candidate inhibitor of the BET bromodomains.
Wyce, A. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget 4 , — Bailey, D.
RVX a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. Stubbs, M. The novel bromodomain and extraterminal domain inhibitor INCB induces vulnerabilities in myeloma cells that inform rational combination strategies.
Endo, J. A phenotypic drug discovery study on thienodiazepine derivatives as inhibitors of T cell proliferation induced by CD28 co-stimulation leads to the discovery of a first bromodomain inhibitor. Cochran, A.
Drug Discov. Zaware, N. Bromodomain biology and drug discovery. Zuber, J. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Bandopadhayay, P. BET bromodomain inhibition of MYC-amplified medulloblastoma. Shu, S.
Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Klingbeil, O. Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents. Cell Death Dis. Boi, M. The BET bromodomain inhibitor OTX affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs.
Clin Cancer Res. Finley, A. Small molecule control of chromatin remodeling. Seal, J. Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET GSKA.
Odore, E. Phase I population pharmacokinetic assessment of the oral bromodomain inhibitor OTX in patients with haematologic malignancies. Potent activity of the bromodomain inhibitor OTX in multiple myeloma. Henssen, A.
Targeting MYCN-driven transcription By BET-bromodomain inhibition. Vázquez, R. Cancer , — PubMed Google Scholar. Xie, F. The BET inhibitor I-BET inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine. Chaidos, A.
Potent antimyeloma activity of the novel bromodomain inhibitors I-BET and I-BET Blood , — Tarantelli, C. BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance.
ESMO Open 3 , e Berenguer-Daize, C. OTX MK , a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models.
Amorim, S. Bromodomain inhibitor OTX in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study.
Lancet Haematol. Berthon, C. Bromodomain inhibitor OTX in patients with acute leukaemia: a dose-escalation, phase 1 study. Lewin, J. Phase Ib trial with birabresib, a small-molecule inhibitor of bromodomain and extraterminal proteins, in patients with selected advanced solid tumors.
Postel-Vinay, S. Piha-Paul, S. Phase 1 study of molibresib GSK , a bromodomain and extra-terminal domain protein inhibitor, in NUT carcinoma and other solid tumors. JNCI Cancer Spectr. BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models.
PLoS ONE 8 , e Faivre, E. Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer. Sheppard, G. Discovery of N-Ethyl[2- 4-fluoro-2,6-dimethyl-phenoxy 1-hydroxymethyl-ethyl phenyl]methyloxo-1H-pyrrolo[2,3-c]pyridinecarboxamide ABBV , a BET bromodomain inhibitor with selectivity for the second bromodomain.
Slavish, P. Bromodomain-selective BET inhibitors are potent antitumor agents against MYC-driven pediatric cancer. Picaud, S. RVX, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain.
Nikolic, D. An evaluation of RVX for the treatment of atherosclerosis. Expert Opin. Drugs 24 , — McLure, K. RVX, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. Gilham, D. Atherosclerosis , 48—57 Nicholls, S. Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial.
Tsujikawa, L. Apabetalone RVX reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism. Google Scholar. Zhang, G. Down-regulation of NF-kappaB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition.
Tanaka, M. Design and characterization of bivalent BET inhibitors. Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer. Cancer Cell 25 , — Hu, Y. BRD4 inhibitor inhibits colorectal cancer growth and metastasis.
Bui, M. Preclinical characterization of BET family bromodomain inhibitor ABBV suggests combination therapeutic strategies. Rhyasen, G. AZD a novel bivalent BET bromodomain inhibitor highly active against hematologic malignancies.
Xu, K. AZD, a novel BRD4 inhibitor, suppresses human thyroid carcinoma cell growth in vitro and in vivo. Mazur, P. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.
Shimamura, T. Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer. Cheng, Z. Inhibition of BET bromodomain targets genetically diverse glioblastoma.
Lockwood, W. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Lenhart, R. Sensitivity of small cell lung cancer to BET inhibition is mediated by regulation of ASCL1 gene expression.
Garcia, P. The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene 35 , — Aggarwal, R.
Ccr Shorstova, T. Fong, C. BET inhibitor resistance emerges from leukaemia stem cells. Synthetic lethal and resistance interactions with BET bromodomain inhibitors in triple-negative breast cancer. Cell 78 , — e Sashida, G.
The loss of Ezh2 drives the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. Rathert, P. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition.
Doebele, R. Acquired resistance is oncogene and drug agnostic. Cancer Cell 36 , — Stratikopoulos, E. Kinase and BET inhibitors together clamp inhibition of PI3K signaling and overcome resistance to therapy. Cancer Cell 27 , — Marcotte, R.
Functional genomic landscape of human breast cancer drivers, vulnerabilities, and resistance. Iniguez, A. Resistance to epigenetic-targeted therapy engenders tumor cell vulnerabilities associated with enhancer remodeling. Cancer Cell 34 , — Echevarria-Vargas, I. Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma.
EMBO Mol. Kurimchak, A. Resistance to BET bromodomain inhibitors is mediated by kinome reprogramming in ovarian cancer. Reprogramming of nucleotide metabolism mediates synergy between epigenetic therapy and MAP Kinase inhibition.
Mct Loganathan, S. Scharschmidt, L. Glomerular prostaglandins, angiotensin II, and nonsteroidal anti-inflammatory drugs. From its ability to cater to a whole range of betting needs to the brand's constant promotion of sizeable and unique free bet bonuses, Bet deserves its position in the upper echelons of the UK gambling industry.
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FC Bayern Munich Arthur ГОООЛ! FC Barcelona Iron ГОООЛ! Paris Saint Germain Andrew ГОООЛ! Manchester City FC Obelix ГОООЛ! As BET proteins are important regulators of transcriptional outputs, it is not surprising that this family of proteins has important roles in homoeostasis and cell survival, and that their dysregulation can promote cancer.
Consequently, attempts have been made to synthesise inhibitors of these proteins—BET inhibitors BETi —as therapeutic agents that restore appropriately regulated gene expression.
We begin this review by outlining the involvement of BET-family members in the hallmarks of cancer, especially avoiding growth suppression and resisting cell death. Subsequently, we will introduce inhibitors of BET-family members, elaborating on biomarkers predicting their efficacy, mechanisms of resistance and enhancing their potency through the use of combination therapies.
BET-family members influence cell cycle progression by activating oncogenes such as MYC , JUNB , CCND1 and CCNA1. Upon being recruited to chromatin, BET-family members engage the mediator complex, which in turn, interacts with the core transcription machinery.
Mediator provides a platform for the association of the pTEFb complex, leading to the phosphorylation of RNA POL II on serine 2, acting as a catalyst for transcriptional elongation. Cell cycle genes are controlled, in part, by the E2F family of transcription factors.
BRD4 binds strongly to the regulatory regions of E2F1 transcriptional targets to enhance their activation, thereby promoting cell cycle progression. Oncogenic roles for BRD4 and BRD3 were first revealed from their propensity to translocate, forming fusion proteins with NUT nuclear protein in testis, also known as NUTM1.
The BRD4—NUT fusion t 15;19 is highly oncogenic and initiates the development of NUT-midline carcinoma NMC , an aggressive tumour with a very poor prognosis. As well as the BRD4—NUT fusion event disrupting normal BRD4 function, 25 it is clear that BRD4 overexpression alone in some contexts might be oncogenic.
This shift from maintaining homoeostasis to promoting proliferation probably arises from the mistargeting of BRD4 to the regulatory regions of oncogenes due to changes in histone acetylation. Studies using BETi indicate this role might be dependent on the recruitment of BET-family members to super-enhancers—large genomic regions containing several enhancers in close proximity—where they aberrantly activate oncogenes.
A short hairpin sh RNA screen revealed that BRD4 is essential for the proliferation of ovarian carcinomas and that BRD4 depletion significantly reduced cancer cell viability. In addition, BRD4 has been implicated in cell invasion and migration—in a breast cancer model, BRD4 inhibition abrogated the invasion of breast cancer cells and downregulated the expression of Snail, a transcription factor involved in the process of epithelial—mesenchymal transition.
As a logical extension of this concept, targeting BET proteins might influence the tumour microenvironment and tumour growth by suppressing pro-inflammatory cytokine release from macrophages within the tumour niche, and the tumour themselves.
To more thoroughly understand the role of BET proteins in tumour progression, it will be necessary to evaluate the impact of elevating the expression of each BET-family member either alone, or in combination, and to subsequently define their relative contribution to various oncogenic processes.
Currently, it is unclear whether all family members contribute equally to neoplastic growth, and whether selectively targeting a subset of family members will result in compensation by active, untargeted, BET proteins.
While BET proteins are commonly overexpressed in cancer, it remains unproven that they act as oncogenic drivers in all cases. Further studies are warranted to define the cancer subtypes in which BET proteins act as tumour promoters as opposed to a non-oncogene addiction.
The intensive development of BETi first gained traction in upon the successful synthesis of two structurally related molecules 34 that competitively bind the acetyl-lysine recognition motif bromodomain of multiple BET proteins 23 , 30 , 35 , 36 , 37 , 38 , 39 Table 1.
We will discuss these two molecules, JQ1 and I-BET GSKA, molibresib, I-BET , at length, followed by a description of recent advances in the development of novel BETi.
The Bradner lab in collaboration with the Structural Genomics Consortium identified a novel thienotriazolodiazepine-based, selective BETi—termed JQ1—which was derived from less potent compounds patented by the Mitsubishi-Tanabe company in and As a result of this tight fit, JQ1 can displace BRD4 from chromatin as confirmed by fluorescence recovery after photobleaching cell assay and by chromatin immunoprecipitation.
The development of JQ1 offered a great opportunity to better understand the biology of BET proteins, validate the oncogenicity of BRD4 and to determine whether BET proteins are bona fide anti-cancer targets.
JQ1 showed anti-cancer properties against NMC models, inducing growth arrest and cell differentiation in NMC-derived cell lines, similar to observations from genetic knockdown studies.
RNA interference screening detected a dependency of acute myeloid leukaemia AML models on BRD4 expression, and JQ1 treatment led to anti-cancer effects in in vitro and in vivo settings by inhibiting cell proliferation and inducing myeloid differentiation.
Subsequent improvements in pharmacological properties have resulted in the synthesis of a JQ1 analogue named TEN JQ2. OTX is a small molecule inhibitor of BRD2, BRD3 and BRD4 that is structurally similar to JQ1.
In preclinical studies, OTX showed efficacy against haematological malignancies including B-cell lymphoma, multiple myeloma and some solid types of cancer such as neuroblastoma and mesothelioma.
In fact, the clinical utility of most BETi evaluated to date has been limited due to unexpected toxicities described in more detail below. The first clinical trials incorporating BETi tested OTX against both haematopoietic and solid cancers described below.
These patients displayed severe dose limited toxicities including gastrointestinal disorders, anaemia, thrombocytopenia, hyperbilirubinaemia, fatigue, headache and back pain. In parallel with the development of JQ1, the benzodiazepine I-BET was developed by GlaxoSmithKline.
I-BET was initially characterised as a chemical means to reduce inflammation. Similar to JQ1, I-BET showed efficacy against multiple myeloma models in vivo. One approach to achieving greater selectivity and potentially reducing unwanted toxicities is to target only one of the two bromodomains of BET proteins.
While most selective BET inhibitors developed thus far target the BD2 domain, there is evidence to suggest that targeting the BD1 domain might be sufficient to elicit anti-proliferative effects, 14 although this concept remains controversial given the potent tumour suppression seen using BD2-selective inhibitors.
Of these, only ABBV and two molecules described within the article, GSK iBET-BD1 and GSK iBET-BD2 showed appreciable selectivity. Their potency against one BD versus the other, differs by a concentration of at least tenfold. An intriguing finding of this study was that targeting only BD1 is sufficient to phenocopy the anti-proliferative effects of pan-BETi in vitro.
ABBV is highly selective for BD2 of BRD2, BRD3 and BRD4, 64 exhibiting several hundred-fold higher affinity for the BD2 over BD1. This sensitivity translated well in vivo, with prostate xenografts responding to as low a dose as 4.
The data for ABBV contrast the reports from Gilan et al, outlined above, indicating that only BD1 is required for anti-proliferative effects of BETi. SJ is another recent, rationally designed, BD2-selective BETi. These findings also contrast with the recent publication from the GlaxoSmithKline group 14 where evidence was presented that targeting BD1 is a primary mechanism whereby BETi achieve growth inhibition.
Moving forward, it will be important for independent groups to repeat the findings of published reports using BD-selective BETi and determine whether targeting BD1 or BD2 will ameliorate the class-specific toxicities of BETi while maintaining their anti-tumour activity.
ABBV Mivebresib is an orally bioavailable, pan-BETi with a pyrrolopyridone core, demonstrates exceptional potency against BRD2, BRD4 and BRDT, with an inhibition constant K i of only 1—2. It is unclear why this molecule has a lower affinity for BRD3, but is likely due to subtle peptide variances between BRD2 and BRD3 within both BDs.
An innovative approach to optimise BETi activity is through synthesis of bivalent BETi, such as AZD, designed to simultaneously recognise, and interact with, both bromodomains of BRD4.
Treatment with BETi has been suggested to be an efficient strategy for multiple preclinical cancer models including NMC, AML, myeloma, lung, breast and pancreatic cancer.
Thus, there is currently an emerging need to carry out BETi research using lower doses in preclinical experiments in order to properly stratify tumours into responders and non-responders. Such approaches will also help future clinical trials avoid undesirable toxicities. We propose that next-generation BETi showing efficacy in vitro at low nanomolar concentrations will be ideal for biomarker studies.
Substantial evidence indicates that the primary target of most BETi, BRD4, is oncogenic—therefore identifying tumour types that are dependent on BRD4 for survival might be one way to identify those tumours that will be most sensitive to BRD4 inhibition.
A topic that is underexplored is whether overexpression of BET-family members themselves influences the sensitivity to BETi.
Although there are many scenarios, it is possible that tumours that overexpress BRD4 depend on its expression for survival. A caveat here involves the selectivity profile of BETi.
Currently, most BETi target all the members of BET subfamily, including BRD2, BRD3, BRD4 and BRDT. Exogenous expression of each BET protein in distinct cell types, either alone or in combination, would help to elucidate tissue-specific oncogenic properties of these chromatin-binding proteins and allow their impact on sensitivity to BETi to be examined.
A key discovery regarding the anti-tumour activity of BETi is that these drugs, including first- and second-generation compounds, silence the expression of MYC in preclinical studies, and it appears that the amplification of MYC family members predicts sensitivity to BETi in multiple tumour types.
However, although MYC is commonly downregulated in cells exposed to BETi, it is not always clear that this event mediates the anti-proliferative effects of BETi, and several studies have shown that MYC does not always act as a mediator of BETi sensitivity.
It is possible that high concentrations of BETi used in preclinical studies have off-target effects that are either exacerbated in MYC-expressing cells, or act through BET-independent pathways to silence MYC. Again, these concerns highlight the need to carry out preclinical studies at relevant concentrations, not far in excess of the IC50 required to dissociate BET proteins from chromatin.
To establish MYC amplification as a robust predictive biomarker, clinical studies demonstrating significant patient responses in MYC -amplified patient cohorts, coupled with a downregulation of MYC in response to drug exposure, would be required.
Clinical data, described below, suggest that MYC suppression holds promise as a pharmacodynamic biomarker.
Three types of biomarkers to BETi treatment exist: predictive biomarkers, biomarkers of resistance and pharmacodynamic biomarkers. Understanding mechanisms through which BRD4-driven transcriptional programmes are regulated is likely to reveal vulnerabilities that could be exploited using BETi.
BRD4 and another bromodomain protein, SMARCA4, independently but concurrently activate gene expression by simultaneously binding to different regulatory elements in their target genes.
These findings demonstrate that the loss of SMARCA4 might act as a potential predictive biomarker for the effectiveness of BETi Fig.
BETi inhibitors act primarily through the repression of oncogenic networks, including those regulated by MYC protein levels.
It should therefore not be surprising that in some cancers, such as AML and triple-negative breast cancer, epigenetic reprogramming to maintain the expression of these oncogenic networks is a mechanism of both intrinsic and acquired resistance.
Many types of cancer are characterised by increased transduction through these classical oncogenic networks. Notably, numerous studies found that BETi inactivate transcriptional programmes involved in RTK signalling exclusively in sensitive cells. On nearly half of these active enhancers, an enrichment for BRD4 binding was concurrently observed.
Notably, based on understanding this underlying mechanism of resistance, it was revealed that these neuroblastoma cell models were sensitive to PI3K inhibitors in combination with BETi.
Likewise, ovarian cancer cells acquiring BETi resistance through long-term culture reprogrammed their kinome to elevate signalling through PI3K and RAS pathways.
However, exome sequencing was not carried out, so de novo activating mutations cannot be excluded. In colorectal cancer models, KRAS mutations do not appear to render tumour cells more resistant to BETi.
In KRAS -mutant-carrying NSCLC models, sensitivity to BETi was reported, but 2. mTOR is a key downstream effector of the PI3K pathway, regulating diverse processes including protein synthesis and cytoskeletal remodelling.
In this model, loss of LKB1 is expected to increase mTOR signalling thereby imparting resistance to BETi. Together, these data suggest that gain-of-function mutations and constitutive activity through the PI3K and RAS signalling axes might act as biomarkers of resistance to BETi in specific types of cancer Fig.
As described below, this information points towards the use of rational combination therapies to overcome this resistance. The stability of BET proteins might also influence their susceptibility to inhibitors.
Remarkably, in endometrial cancer, some SPOP SRD mutations, such as RQ, lead to an enhanced association between SPOP and BET-family members, which results in increased ubiquitylation, decreased BET protein levels and enhanced sensitivity to BETi.
Overall, SPOP mutations hold great promise as biomarkers of both resistance and sensitivity to BETi. These studies reinforce the notion that BRD4 levels within tumours modulate the responsiveness to BETi. The data also suggest that the activity of BET proteins might be regulated by proteasomal degradation across tissue types, which opens new therapeutic perspectives.
Especially relevant might be targeting BET proteins, either individually or combinatorially, using a proteolysis targeting chimera PROTAC, reviewed in ref. Pharmacodynamic biomarkers enable the clinical monitoring of drug activity in vivo, ideally using simple PCR or ELISA-based assays that act in lieu of more complex approaches to measure the accumulation of an administered drug within plasma or the tumour itself.
Identifying robust pharmacodynamic biomarkers for BETi in preclinical settings will undoubtedly facilitate the optimisation of their clinical utility. Generating such biomarkers might be enhanced through the preclinical use of orthotopic xenografts that mimic a relevant tumour microenvironment, thereby more accurately predicting drug response in a time- and dose-dependent manner.
Upregulation of HEXIM1 has been identified as a potential pharmacodynamic biomarker in numerous tumour xenografts and whole blood samples in response to ABBV treatment Fig.
A small clinical trial showed a trend for both MYC repression and an increase in HEXIM1 in the plasma of patients treated with the BETi BAY for mixed, refractory malignancies. This is below administered drug levels eliciting dose-limiting toxicities. This may cast some doubt on the necessity for BETi to lower MYC transcription in order to provoke an anti-tumour response.
Another preclinical study reported that MYC and HEXIM1 act most robustly as tumour-based pharmacodynamic biomarkers for BETi and that the corresponding mRNAs did not show optimal correlation with drug accumulation within blood samples.
The study from Yeh et al. This is especially relevant for CCR2, that is known to recruit myeloid-derived suppressor cells to the tumour niche, which in turn, promotes tumour growth. After extensive preclinical evaluation, but in the absence of robust predictive biomarkers, multiple clinical trials of BETi against solid and haematological types of cancer have been initiated.
To date, ~25 clinical trials are either ongoing or have been completed Table 2. With the exception of NMC, these trials are not targeting specific molecular subtypes, and this lack of biological rationale, plus unexpected toxicities, might limit clinical efficacy in the short term.
Strong results from the preclinical evaluation of BETi in multiple myeloma mled to elevated expectations for achieving clinical responses in this malignancy. The first published clinical trials of BETi all used the widely studied drug OTX MK Among five patients with MYC-positive DLBCL, only one showed a favourable outcome to BETi exposure.
However, this dose might not be universally achievable because almost all of the patients in this trial displayed dose-limiting toxicities, including thrombocytopenia, anaemia, neutropenia, gastrointestinal events and fatigue. Based on published clinical data, these toxicities appear to be common for this class of drugs regardless of the type of cancer being treated or the chemical structure of the BETi being tested.
Once maximum drug activity is identified in the plasma or intratumorally, higher doses are likely to elicit strong off-target effects. As described above, NMC is characterised by BRD4 fusions leading to aberrant BRD4 activity. Again, based on preclinical data, expectations that BETi would show efficacy against these tumours were high and, consequently, the first published clinical trial using BETi was focused on NMC.
Clinical responses were observed in two patients, but all four patients succumbed to their disease between 5 and 19 months post-diagnosis. Complementing this study, Lewin et al.
Partial responses have also been described for NMC patients treated with the I-BETA molibresib. In addition to MYC and BRD4—NUT-driven malignancies, BETi have been tested against several AMLs and diverse solid tumours. In an initial study of OTX in a cohort of 41 patients with AML, 59 three patients showed partial responses and two patients showed a complete response lasting 2—5 months.
Notably, however, an attempt to identify potential biomarkers including mutations in 42 genes failed to uncover any clear molecular pathologies among responders.
Although published reports of the use of BETi against solid tumours have not met expectations, responses have been observed, again underscoring a need for predictive biomarkers. Perhaps the most promising preclinical data against solid tumours beyond NMC have come from prostate cancer models.
This study included patient cohorts harbouring both solid and haematological tumours. In total, 65 patients were enrolled, including those with NMC, small cell- and non-small lung cancer, triple-negative breast cancer TNBC , CRPC, colorectal cancer, neuroblastoma and multiple myeloma.
While complete responses were not reported, four NMC patients had confirmed and unconfirmed partial responses and one TNBC patient achieved unconfirmed partial response. Based on these data, we predict that BETi might play an important clinical role in the management of NMC.
However, it is clear that predictive biomarkers and, most likely, combinatorial approaches, will be essential moving forward and, perhaps more importantly, it will be critical to overcome in-class dose-limiting toxicities. BET proteins are important for multiple cellular processes required for homoeostasis, which might explain why complete bromodomain inhibition leads to unexpected toxicities.
Advances in the medicinal chemistry of BETi might be required to dissociate anti-cancer effects from the inhibition of physiological pathways required for homoeostasis. The necessity of using such high doses to combat cancer proliferation strongly suggests a high level of intrinsic resistance to these compounds across tumour types that has not been widely studied or appreciated.
The precise mechanisms of intrinsic resistance to BETi remain unclear, but multiple studies suggest that the activation of oncogenic signalling pathways including those mediated by PI3K and RAS might be involved and that repression of these pathways might act as key mediators of BETi activity.
We suggest that, consequently, these pathways also play a role in intrinsic BETi resistance and could therefore be targeted in conjunction with the use of BETi.
Several studies report the PI3K pathway as a determining factor influencing BETi both intrinsic and acquired resistance, and suggest that this resistance could be successfully overcome through the combination treatment using BETi and PI3K inhibitors.
As described below, a better understanding the mechanisms of resistance mediated by constitutive signalling through PI3K and MAPK pathways will probably reveal new therapeutic options for these patients.
Multiple studies demonstrate that combining BETi with tyrosine kinase inhibitors effectively overcomes both intrinsic and acquired resistance to these drugs in several types of cancer. A chemical combinatorial screening of JQ1 with around compounds aimed at finding effective small molecule combination therapies with BETi revealed PI3K inhibitors to be the most potent partners against neuroblastoma both in vitro and in animal models.
Melanomas bearing NRAS mutations frequently have high BRD4 mRNA and protein expression levels, which are associated with a poor outcome. The combined treatment downregulated proteins implicated in cell cycle regulation and apoptosis.
Recent evidence indicates that cell cycle regulation resulting from the combination of BETi with MAPK inhibitors may stem from a broad repression of nucleotide metabolism in ovarian cancers. Moving forward, it will be important to examine whether this mechanism is relevant to other cancer models sensitive to this combination.
About half of all recurrent TNBC express high levels of n-MYC. It remains to be experimentally proven which, if any, of these correlates are responsible for the observed growth inhibition. In PDX models of TNBC, intermediate or high levels of n-MYC predicted response to the synergistic combination of trametinib with either JQ1 or another BETi, INCB, whereas PDX models with low levels of n-MYC were more resistant.
As stated above, the half-life of JQ1 in vivo is quite short, and high doses are generally required to achieve effects. Additional combinations using BETi also show promise. KRAS mutations are very prevalent in pancreatic ductal adenocarcinoma PDAC and is associated with a very poor prognosis.
That being said, independent reports have supported the applicability of this combination in vivo, using either a MYC-driven lymphoma model or against a neuroblastoma model.
As stated previously, BET proteins might act as oncogenes, at least in part, through the activation of genes involved in cell cycle progression.
As such, it would be logical to combine BETi with inhibitors of CDKs. This approach has been explored successfully in NMC. An interesting combination of BETi with vitamin C was demonstrated to be effective using both in vitro and in vivo TNBC models.
In this study, simultaneous treatment resulted in a decrease in histone acetylation, perhaps consistent with the findings of efficacy between BETi and HDAC inhibitors.
This strategy of combining BETi with vitamin C not only in TNBC, but also in melanoma significantly improved the EC50 of BETi by reducing it to a nanomolar range. Even though responses differ across tissue types, the cell response to BETi is generally cytostatic in nature, resulting in delayed cell cycle progression.
Thus, it might be logical to complement this cytostatic response with promoters of an apoptotic response. Supporting this idea are a number of studies showing synergy between several BETi and the BCL-2 inhibitor venetoclax ABT against haematopoietic malignancies.
The combination of inhibitors of poly-ADP ribose polymerase PARP with BETi has shown great promise, instigating a loss of proliferation across many cell types, including ovarian, breast and pancreatic cancer models both in vitro and in vivo.
The development of BETi has provided important insights into the key role of BET proteins in the transcriptional control of proto-oncogenes, and highlighted the potential of these proteins as therapeutic targets. Preclinical studies have demonstrated a remarkable anti-proliferative activity of BETi against tumours, including several incurable subtypes.
It is our opinion that a lack of biomarkers predicting sensitivity to BETi, coupled with the use of non-clinically relevant doses in preclinical studies, is limiting the application of these agents in clinical practice.
Further research and mechanistic studies will help to identify such biomarkers, and the development of novel, highly selective bromodomain inhibitors will help prevent toxicities.
Finally, exciting new data indicate that, in the long term, BETi are likely to hold the most clinical potential as a part of combinatorial regimens. Hanahan, D. Hallmarks of cancer: the next generation.
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Bhagwat, A. BET bromodomain inhibition releases the mediator complex from select cis-regulatory elements. Cell Rep. Jang, M. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription.
Cell 19 , — Gilan, O. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science , — Yang, Z. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression.
Cell Biol. Sinha, A. Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A. Mochizuki, K. The bromodomain protein Brd4 stimulates G1 gene transcription and promotes progression to S phase. Chapuy, B. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma.
Cancer Cell 24 , — Delmore, J. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Peng, J. Brd2 is a TBP-associated protein and recruits TBP into E2F-1 transcriptional complex in response to serum stimulation.
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Oncogene 33 , — BET has launched several spin-off networks over the years, including BET Her formerly known as "BET on Jazz", then "BET J" and later "Centric" , BET Jams formerly known as "MTV Jams" , and BET Soul formerly known as "VH1 Soul" , alongside SHO×BET, a premium Showtime multiplex network.
In May , a BET-branded channel was launched on Pluto TV , which was owned by ViacomCBS in March The service launched in the United States in Fall with First Wives Club which was originally planned to launch on Paramount Network before being shifted to BET announced as one of the service's original series.
BET Gospel is a television network in the United States that launched on July 1, , and provides gospel and religious programming. The network, a spin-off of BET Black Entertainment Television , mixes new and classic shows as well as original gospel-oriented programming.
BET Gospel previously ran on an automated loop schedule. In , the channel was updated with its programming now composing of recent uplifting music videos, as well as gospel-themed series and specials.
BET Jams is an American pay television network airing hip-hop and urban contemporary music videos on a thrice-daily automated wheel schedule of eight hours outside of temporary "roadblock" closures during Paramount Global awards events, with all of its programming currently denoted in hour blocks as BET Jams — Music Videos within electronic program guide listings.
The channel launched on May 1, , as MTV Jams, and carried that name until October 5, , and was placed under BET's purview as MTV drifted away from music programming. The network space itself launched on August 1, , as MTVX , carrying modern rock videos, and was re-focused around hip-hop music on that date, to some controversy from MTVX's former viewers.
BET Hip-Hop is a music video network owned by BET Networks which is exclusive to digital cable systems. It formerly aired some of BET's original programming such as Rap City , ComicView and the network's video countdown programs.
After the relaunch of the former MTV Jams as BET Jams which has much wider distribution , the channel's programming was shifted to an automated playlist made up of BET's library of older hip-hop videos.
As part of Viacom 's restructuring plan, the network was speculated to slowly wind down operations over time.
BET UK first transmitted on Videotron now known as Virgin Media and several other subscription providers from until In May by Ofcom , BET International Inc. was given a license to rebroadcast in the United Kingdom. BET International is the first international version of the channel and is available in Europe, Africa and the Middle East through satellite providers.
BET launched on February 27, , on Sky channel and began to be carried by Freesat channel on August 8, BET International shows with a mix of content from the main BET channel and locally produced shows.
An exclusive, but temporary, HD version of the channel was made to show the BET Awards on Freesat EPG BET is additionally an associate member of the Caribbean Cable Cooperative.
BET launched an app called BET Play allowing international access to BET content in over countries in June The channel was shut down on April 8, , with its content moved to My5 and Pluto TV. BET became available in Canada on October 17, , on most pay television providers.
The Canadian feed mirrors the U. feed, though certain television programs and films are blacked out. Until , they were replaced with repeats of old music video blocks namely BET Music , The Pull Up and BET Now.
As of May , the feed now airs current music videos and other acquired sitcoms and films in place of blacked-out programs. Introduced on November 17, Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item.
Download as PDF Printable version. In other projects. Wikimedia Commons. American basic cable channel owned by Paramount. This article is about the television channel. For other uses, see Bet.
Television channel. The network's logo from to , still used by BET Networks the star was rendered as an outline from its debut until Main article: List of programs broadcast by BET. Paramount Players Tyler Perry Studios.
Paramount Players Will Packer Productions. Lionsgate Films Genius Minds Pictures. Main article: BET International. Main article: BET France. Deadline Hollywood. Retrieved February 25, April 2, Are You Watching? TV by the Numbers.
Archived from the original on February 23, Retrieved February 24, Fortune Small Business. Retrieved September 8, BET Networks. Archived from the original on September 12, Retrieved September 12, Archived from the original on June 28, Retrieved July 1, Miller's Design Journey".
AIGA the professional association for design. November 16, Retrieved June 23, The Billion Dollar BET: Robert Johnson and the Inside Story of Black Entertainment Television. ISBN Contemporary Black Biography. Retrieved July 2, Petersburg Times. Retrieved December 30, The Washington Post.
Black Voices. Archived from the original on December 17, Retrieved July 27, Retrieved November 20, The Hollywood Reporter. Retrieved March 7, Retrieved July 26, Archived from the original on September 9, May 24, Retrieved December 29, March 30,
noun as in game vet chance; money casino roulette. Words ib in bet bet are casino roulette gold bets synonyms, but are associated with the word bet. Browse related words to learn more about word associations. noun as in gamble, risk. noun as in chance, speculation. verb as in take a chance on winning. verb as in gamble, risk.
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