BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer

Asangani, Irfan A.; Wilder-Romans, Kari; Dommeti, Vijaya L.; Krishnamurthy, Pranathi M.; Apel, Ingrid J.; Escara‐Wilke, June; Plymate, Stephen R.; Navone, Nora M.; Wang, Shaomeng; Feng, Felix Y.; Chinnaiyan, Arul M.

doi:10.1158/1541-7786.mcr-15-0472

Cited by 134 publications

(116 citation statements)

References 23 publications

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“…Importantly, we and others have shown that BET inhibition has a dual mechanism of action, suppressing not only AR transcriptional activity but also AR gene transcription (Chan et al 2015, Raina et al 2016. This finding, combined with the mapping of the BRD4 interaction surface to the AR-NTD, suggests that BET inhibitors would have activity in CRPC driven by AR-LBD mutants and/or AR-Vs, a prediction that has been experimentally substantiated (Chan et al 2015, Asangani et al 2016, Raina et al 2016.…”

Section: Targeting Androgen Receptor Coregulatorssupporting

confidence: 66%

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

138

122

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The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

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Section: Targeting Androgen Receptor Coregulatorssupporting

confidence: 66%

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

138

122

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“…This includes reports of antitumor effects using BET bromodomain inhibitors in MM(Chaidos et al, 2014 , Siu et al, 2016), ovarian cancer (Zhang et al, 2016), gastric cancer (Montenegro et al, 2014), childhood sarcoma (Bid et al, 2016), and triple negative breast cancer (da Motta et al, 2016; Shu et al, 2016). Acquired resistance to BET inhibitors have also been reported (Fong et al, 2015; Kumar et al, 2015; Rathert et al, 2015), with recent studies suggesting combinatorial drug treatment to overcome resistance mechanisms (Asangani et al, 2016; Kurimchak et al, 2016; Yao et al, 2015). In addition to efficacy, the nonclinical safety of BET inhibition has also been examined.…”

Section: Introductionmentioning

confidence: 99%

Replication Study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc

Aird

Kandela

Mantis

2017

eLife

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In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" (Delmore et al., 2011). Here we report the results of those experiments. We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulated MYC transcription, which is similar to what was reported in the original study (Figure 3B; Delmore et al., 2011). Efficacy of (+)-JQ1 was evaluated in an orthotopically xenografted model of MM. Overall survival was increased in (+)-JQ1 treated mice compared to vehicle control, similar to the original study (Figure 7E; Delmore et al., 2011). Tumor burden, as determined by bioluminescence, was decreased in (+)-JQ1 treated mice compared to vehicle control; however, while the effect was in the same direction as the original study (Figure 7C-D; Delmore et al., 2011), it was not statistically significant. The opportunity to detect a statistically significant difference was limited though, due to the higher rate of early death in the control group, and increased overall survival in (+)-JQ1 treated mice before the pre-specified tumor burden analysis endpoint. Additionally, we evaluated the (−)-JQ1 enantiomer that is structurally incapable of inhibiting BET bromodomains, which resulted in a minimal impact on MYC transcription, but did not result in a statistically significant difference in tumor burden or survival distributions compared to treatment with (+)-JQ1. Finally, we report meta-analyses for each result.DOI: http://dx.doi.org/10.7554/eLife.21253.001

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“…Members of this group are JQ1 and a derivative OTX015 [41, 42, 43, 44]. In glioblastoma c-myc is also up-regulated and therefore represents a potential target for BET – inhibitors.…”

Section: Bh3-mimetics Targeting Bcl-xl Bcl-2 and Bcl-wmentioning

confidence: 99%

Targeting intrinsic apoptosis and other forms of cell death by BH3-mimetics in glioblastoma

Karpel‐Massler¹,

Ishida

Zhang

et al. 2017

Expert Opinion on Drug Discovery

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Introduction: Novel approaches to treat malignant brain tumors are necessary since these neoplasms still display an unfavorable prognosis. Areas covered: In this review, the authors summarize and analyze recent preclinical data that suggest that targeting intrinsic apoptosis may be a suitable strategy for the treatment of malignant gliomas. They focus on the anti-apoptotic Bcl-2 family members of proteins and the recent drug developments in that field with a special focus on BH3-mimetics. With the discovery of BH3-mimetics that interfere with anti-apoptotic Bcl-2 family members in the low nanomolar range significant excitement has been generated towards these class of inhibitors, such as ABT-737, ABT-263 and the most recent successor, ABT-199 which is most advanced with respect to clinical application. The authors discuss the more recent selective inhibitors of Bcl-xL and Mcl-1. Concerning Mcl-1, these novel classes of inhibitors have the potential to impact malignant gliomas since these tumors reveal increased levels of Mcl-1. Expert opinion: The recent development of certain small molecules raises significant hope that intrinsic apoptosis might soon be efficiently targetable for malignancies of the central nervous system. That being said, additional studies are necessary to determine which of the BH3-mimetics might be most suitable.

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BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer

Cited by 134 publications

References 23 publications

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Replication Study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc

Targeting intrinsic apoptosis and other forms of cell death by BH3-mimetics in glioblastoma

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