The BET Bromodomain Inhibitor I-BET151 Acts Downstream of Smoothened Protein to Abrogate the Growth of Hedgehog Protein-driven Cancers

Long, Jun; Li, Bin; Rodríguez-Blanco, Jezabel; Pastori, Chiara; Volmar, Claude‐Henry; Wahlestedt, Claes; Capobianco, Anthony J.; Bai, Feng; Pei, Xin-Hai; Ayad, Nagi G.; Robbins, David J.

doi:10.1074/jbc.m114.595348

Cited by 102 publications

(94 citation statements)

References 35 publications

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“…However, only the interaction of GLI1 and BET proteins was sensitive to BETi, indicating that GLI1-BET complexes are largely responsible for the bromodomain-dependent GLI activity observed in PDAC cells and suggests a bromodomain-independent mechanism by which BET proteins associate with GLI2. Decreases in GLI activity after BET bromodomain inhibition have also been reported in mouse fibroblasts and mouse models of medulloblastoma (22,23). However these changes in GLI activity involve the direct regulation of GLI mRNA expression and ultimate control of corresponding protein levels by BET proteins.…”

Section: Discussionmentioning

confidence: 66%

Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment

Huang

Nahar

Nakagawa

et al. 2016

Clinical Cancer Research

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Purpose The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. Experimental design In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, immunohistochemistry, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. Results In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacological inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in down-regulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer associated fibroblast content of tumors in both GEM and xenograft tumor models. Conclusions Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Translational Relevance Pancreatic ductal adenocarcinoma is extraordinarily chemoresistant and the abundant stromal content of these tumors contributes to the ineffective treatment of this disease. Current approaches in the treatment of PDAC are largely ineffective and utilize drugs that target either the neoplastic cells or the stroma of this disease. This study reveals the broad dependence of pancreatic cancer cell lines and tumor models on the activity of the BET family of chromatin adaptors. BET proteins contribute to PDAC biology by regulating multiple key nodal pathways of this disease, including the direct and indirect regulation of GLI, a family of transcription factors that plays key roles in both epithelial and stromal cells of PDAC tumors. Therapeutic inhibition of BET proteins provides a unique opportunity to simultaneously target both the stromal and neoplastic cells of PDAC.

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Section: Discussionmentioning

confidence: 66%

Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment

Huang

Nahar

Nakagawa

et al. 2016

Clinical Cancer Research

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“…x TIPS-1241; No. of Pages 12 in vitro and in vivo (Table 1) [66]. Notably, BRD4 has been found overexpressed in PDAC cell lines, being able to sustain a high proliferative growth rate and chemoresistance [67].…”

Section: Reviewmentioning

confidence: 98%

Targeting GLI factors to inhibit the Hedgehog pathway

Infante

Alfonsi

Botta

et al. 2015

Trends in Pharmacological Sciences

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Hedgehog (Hh) signaling has emerged in recent years as an attractive target for anticancer therapy because its aberrant activation is implicated in several cancers. Major progress has been made in the development of SMOOTHENED (SMO) antagonists, although they have shown several limitations due to downstream SMO pathway activation or the occurrence of drug-resistant SMO mutations. Recently, particular interest has been elicited by the identification of molecules able to hit glioma-associated oncogene (GLI) factors, the final effectors of the Hh pathway, which provide a valid tool to overcome anti-SMO resistance. Here, we review results achieved in developing GLI antagonists, explaining their mechanisms of action and highlighting their therapeutic potential. We also underline the relevance of structural details in their discovery and optimization.

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“…One of the most promising class of drugs are SMO inhibitors, which are already in phase II clinical trials for a number of cancers including medulloblastoma [69–71]. Unfortunately, acquired resistance is inevitable in both animals and humans; a recurrent mutation in a conserved aspartic acid residue within the G protein–coupled receptor domain of SMO has been shown to disrupt the functionality of inhibitors, leaving Shh signalling intact [71, 72]. Furthermore, the drug is only effective for patients with alterations within or upstream of SMO, and therefore high-risk children with amplifications of MYCN and GLI2 would not be able to benefit from this treatment [17].…”

Section: Therapiesmentioning

confidence: 99%

“…BRD4 is a bromodomain protein which binds to ε-N-lysine acetylation motifs on open chromatin and is known to facilitate transcription at promoter regions of key transcription factors such as GlI2 and MYC. Treatment of SHH with BRD4 inhibitors has shown great promise in pre-clinical models even in the presence of SMO drug resistance mutations [72, 73]. …”

Section: Therapiesmentioning

confidence: 99%

Genetic and molecular alterations across medulloblastoma subgroups

2015

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Medulloblastoma is the most common malignant brain tumor diagnosed in children. Over the last few decades advances in radiation and chemotherapy have significantly improved the odds of survival. Nevertheless, one third of all patients still succumb to their disease, and many long-term survivors are afflicted with neurocognitive sequelae. Large scale multi-institutional efforts have provided insight into the transcriptional and genetic landscape of medulloblastoma. Four distinct subgroups of medulloblastoma have been identified, defined by distinct transcriptomes, genetics, demographics and outcomes. Integrated genomic profiling of each of these subgroups has revealed distinct genetic alterations, driving pathways and in some instances cells of origin. In this review we highlight, in a subgroup specific manner, our current knowledge of the genetic and molecular alterations in medulloblastoma and underscore the possible avenues for future therapeutic intervention.

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The BET Bromodomain Inhibitor I-BET151 Acts Downstream of Smoothened Protein to Abrogate the Growth of Hedgehog Protein-driven Cancers

Cited by 102 publications

References 35 publications

Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment

Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment

Targeting GLI factors to inhibit the Hedgehog pathway

Genetic and molecular alterations across medulloblastoma subgroups

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