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BET Proteins As Targets for Anticancer Treatment Published OnlineFirst December 20, 2017; DOI: 10.1158/2159-8290.CD-17-0605 REVIEW BET Proteins as Targets for Anticancer Treatment Anastasios Stathis 1 and Francesco Bertoni 1 , 2 ABSTRACT Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression and are involved in cancer pathogenesis. Over the last years, several BET inhibitors have been developed and clinically tested. Results from the fi rst clinical trials show limited single-agent activity in a small subset of patients with hematologic malignancies and in NUT carcinoma. Adverse events have been observed and may limit treatment compliance. Here, we review the preclinical rationale for targeting BET proteins in cancer and the preliminary results from clinical trials, and outline future directions for the use of BET inhibitors as antitumor agents. Signifi cance: BET inhibitors represent a new class of anticancer agents. Results from the fi rst clinical trials confi rm the antitumor potential of BET inhibitors, but their effi cacy as single agents seems to be limited. Based on preclinical data, combination therapies with other anticancer agents and the devel- opment of a new generation of compounds may open new possibilities for targeting BET proteins as effective anticancer strategies. Cancer Discov; 8(1); 24–36. ©2017 AACR. BET PROTEINS AS EPIGENETIC READERS factor TWIST, involved in mesoderm formation ( 9 ); to acet- ylated RelA, regulating the transcriptional activity of NF- Human cells contain tens of thousands of active promoter kappaB ( 10 ); or to acetylated ERG in acute myeloid leukemia regions and enhancer regions that are highly cell-type depend- (AML) cells ( 8 ). BET proteins can also bind other proteins, ent, and a few hundred superenhancers, which are clusters of including transcription factors, in a bromodomain-independent enhancers characterized by a very high binding of Mediator manner, such as the binding of BRD4 to FLI1, MYB, SPI1 complexes and master transcription factors ( 1–3 ). For exam- (PU.1), CEBPA, CEBPB ( 8 ), or p53 ( 11 ). Finally, BET can also ple, in a multiple myeloma cell line, Loven and colleagues have have kinase activity ( 9 ), a function not yet fully understood. identifi ed approximately 10,000 annotated active transcription The fundamental role of BET proteins is demonstrated start sites, 8,000 enhancers, and 308 superenhancers ( 1 ). Super- by the fact that homozygous deletion of BRD2 or BRD4 is enhancer-associated transcripts comprise the key cell identity embryonic lethal ( 12–15 ). BET proteins, acting as scaffolds genes and are expressed at higher levels than genes associated to recruit other proteins, are localized at promoters and with normal enhancers ( 2–4 ). especially at enhancers of active genes, participating with the Bromodomain and extraterminal domain (BET) proteins are Mediator complex, as master transcription elongation factors epigenetic readers characterized by the presence of two tandem (refs. 4, 5, 7, 16 , 17 ; Fig. 1 ). BET proteins match the chromatin bromodomains (BD1 and BD2), an extraterminal domain (ET), acetylation status with transcriptional elongation via dis- and a C-terminal domain (CTD; ref. 5 ). They comprise the placing HEXIM1/7SK snRNP from the transcription elonga- ubiquitously expressed BRD2, BRD3, and BRD4 and the testis- tion factor b Cyclin T1/CDK9 complex (P-TEFb), allowing restricted BRDT, and mainly recognize acetylated lysine of his- the latter to activate RNA polymerase II via phosphorylation tone 4 ( 5, 6 ). BET proteins also recognize acetylated nonhistone at serine 2 (refs. 4, 7, 16, 18 ; Fig. 1 ). In addition, especially at proteins, including different transcription factors ( 5–8 ). Exam- enhancers, BET proteins also recruit the demethylase JMJD6, ples are the binding of BRD4 to the acetylated transcription which induces degradation of 7SK snRNP and P-TEFb acti- vation ( 7, 9, 19 ). However, the exact role of BET proteins in the transcription machinery has yet to be elucidated. 1 Oncology Institute of Southern Switzerland, Bellinzona, Switzerland . Data obtained studying BRD4 in AML cells show that the 2 Università della Svizzera italiana, Istituto Oncologico di Ricerca, Bellin- zona, Switzerland. recruitment of BET proteins at promoters and enhancers is mediated by transcription factors mainly due to the binding Corresponding Author: Anastasios Stathis, Oncology Institute of South- ern Switzerland, Ospedale San Giovanni, 6500 Bellinzona, Switzerland. of BRD4 to p300/CBP acetyltransferase–mediated acetylated Phone: 41-091-811-8931; Fax: 41-091-811-9182; E-mail: anastasios.stathis lysine residues ( 8 ). Moreover, a recent publication provided @eoc.ch evidence that BRD4 is fundamental for the creation of the doi: 10.1158/2159-8290.CD-17-0605 productive transcription elongation factor complex but not © 2017 American Association for Cancer Research. for the direct recruitment of P-TEFb ( 4 ). 24 | CANCER DISCOVERY JANUARY 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst December 20, 2017; DOI: 10.1158/2159-8290.CD-17-0605 Anticancer Therapy Using BET Inhibitors REVIEW Active genes Med P-TEFb TF Med P-TEFb TF RNA RNA BRD4 BRD4 Pol II Pol II Ac Ac Ac Ac Superenhancers Promoters Med P-TEFb TF RNA Active BRD4 Pol II genes Med P-TEFb TF RNA BRD4 Pol II BET-i BET-i Ac Ac Ac Ac Superenhancers Promoters Figure 1. Schematic representation of the mechanism of action of BET inhibitors. BET proteins recognize acetylated lysine of histone 4 and act as scaffolds to recruit many other proteins to promoters and at enhancers of active genes, especially at the superenhancers of key genes, driving the transcription process. Exposure of tumor cells to BET inhibitors reduces the levels of BRD4 at enhancers and at promoters at a genome-wide level, but the reduction is more marked at superenhancers, and the genes associated with superenhancers undergo stronger and faster downregulation than genes regulated by standard enhancers. Examples of such genes are MYC, NMYC, IL7R, FOSL1, AR, ER, BCL2, BCL6, PAX5, CDK4, and CDK6. BET-i, BET inhibi- tor; Med, mediator; TF, transcription factor. PRECLINICAL RATIONALE FOR TARGETING a major pathogenetic driver of cellular transformation (26). BET PROTEINS IN HUMAN CANCER Silencing of the BRD4–NUT fusion gene results in differen- tiation and growth arrest of NUT carcinoma cells (26). More Several lines of evidence coming from preclinical studies importantly, the displacement of the BRD4 oncoprotein from indicate a role of BET proteins in human cancer and have pro- chromatin using the BET inhibitor JQ1 has antiproliferative vided the rationale for targeting BET proteins as a strategy for activity with squamous differentiation in BRD4-dependent the development of new anticancer drugs. Genetic screening cell lines and patient-derived xenograft models (27). programs performed in different tumor types have recurrently Exposure of tumor cells to BET inhibitors results in a identified the genes encoding BET proteins as genes on which genome-wide reduction of the levels of BRD4 at enhanc- neoplastic cells depend for their survival (20–23). Overexpres- ers and at promoters with important changes at the gene sion of BRD2/BRD4 genes also occurs in human cancers (23, 24). expression level, largely represented by a downregulation of Finally, the most direct and clear evidence of the involvement transcripts (refs. 1, 4, 17, 27–30; Fig. 1). Downregulation of of BET proteins in the pathogenesis of human cancer derives key oncogenes that are associated with superenhancers, such from NUT carcinoma, a rare and aggressive form of undiffer- as MYC, represents a possible mechanism of the antitumor entiated squamous cell carcinoma that mainly affects midline activity of BET inhibitors (1). Biomarkers of exposure to structures. Initially thought of as a disease of children and BET inhibitors have been proposed, such as transcriptional adolescents, NUT carcinoma can actually occur at any age. modulation of MYC and HEXIM1 (31, 32) and CCR1 and NUT carcinoma is genetically defined by chromosomal rear- IL1RN (33). rangements involving the NUT gene on chromosome 15q14 Signatures of exposure to BET inhibitors are relatively fused to the BET gene BRD4 on chromosome 19p13.1, or less similar among different tumor types (31, 34, 35), but specific commonly to other genes, including BRD3 and NSD3BRD changes predominate in different cellular contexts in which (25, 26). The translocation creates an in-frame BRD4–NUT BET inhibitors directly affect key tissue- or cancer-specific oncogene driven by the BRD4 promoter that is considered genes, mainly transcription factors (1, 4, 8, 28, 29, 31, 36–42). JANUARY 2018 CANCER DISCOVERY | 25 Downloaded from cancerdiscovery.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst December 20, 2017; DOI: 10.1158/2159-8290.CD-17-0605 REVIEW Stathis and Bertoni Examples of key genes are MYC ( 4, 20, 22, 24 , 35–38, 43–47 ), were two seminal papers demonstrating that BET inhibitors AR and TMPRSS2 –ETS fusion genes ( 48, 49 ), FOSL1 ( 50, 51 ), can induce terminal differentiation and apoptosis in pre- E2F2 ( 38 ), ITK ( 31 ), IL7R ( 35, 38, 44, 50 ), TERT ( 24, 46 ), BCL2 clinical NUT carcinoma models ( 27 ) and can have important ( 22, 24, 43, 46 ), CDK6 ( 17, 22, 38, 43 ), IRF4 ( 24, 37, 45 ), and anti-infl ammatory activity ( 53 ). Many other publications
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