Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma

Siegel, Matthew B.; Liu, Selina Qiuying; Davare, Monika A.; Spurgeon, Stephen E.; Loriaux, Marc; Druker, Brian J.; Scott, Emma C.; Tyner, Jeffrey W.

doi:10.18632/oncotarget.4214

Cited by 42 publications

(33 citation statements)

References 44 publications

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“…Indeed, we and other investigators have recently demonstrated that inhibitors targeting cell-signaling molecules, the proteasome, components of the DNA damage response and HDAC synergize with BETIs to kill B-cell malignancies. 13 , 14 , 15 , 16 , 17 , 18 , 19 HDAC and BETI combination treatment is also effective in melanoma 20 but whether any of the other therapies would be effective is not known.…”

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confidence: 99%

BET bromodomain inhibitors synergize with ATR inhibitors in melanoma

et al. 2017

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Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.

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confidence: 99%

BET bromodomain inhibitors synergize with ATR inhibitors in melanoma

et al. 2017

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“…For those compounds newly included in this study, comparably low IC 50 s, based on their previous reports in other cancers, were also listed ( Supplementary Table S4; refs. 16,[38][39][40][41]. As shown in Fig.…”

Section: High-throughput Sirna and Small-molecule Inhibitor Library Smentioning

confidence: 96%

Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma

Sun

Lin

Cao

et al. 2017

Clinical Cancer Research

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Ewing sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TK) and associated pathways are continuously activated in many malignancies, including EWS; these enzymes provide candidate therapeutic targets. Two high-throughput screens (a siRNA library and a small-molecule inhibitor library) were performed in EWS cells to establish candidate targets. Spleen tyrosine kinase (SYK) phosphorylation was assessed in EWS patients and cell lines. SYK was inhibited by a variety of genetic and pharmacological approaches, and SYK-regulated pathways were investigated by cDNA microarrays. The transcriptional regulation of MALAT1 was examined by ChIP-qPCR, luciferase reporter, and qRT-PCR assays. SYK was identified as a candidate actionable target through both high-throughput screens. SYK was highly phosphorylated in the majority of EWS cells, and SYK inhibition by a variety of genetic and pharmacologic approaches markedly inhibited EWS cells both and Ectopic expression of SYK rescued the cytotoxicity triggered by SYK-depletion associated with the reactivation of both AKT and c-MYC. A long noncoding RNA, MALAT1, was identified to be dependent on SYK-mediated signaling. Moreover, c-MYC, a SYK-promoted gene, bound to the promoter of MALAT1 and transcriptionally activated MALAT1, which further promoted the proliferation of EWS cells. This study identifies a novel signaling involving SYK/c-MYC/MALAT1 as a promising therapeutic target for the treatment of EWS. .

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“…3) is a BET bromodomain inhibitor that has shown synergetic activity with drugs that have already been clinically approved for cancer treatment. Multiple myeloma cells resistant to bortezomib and melphalan treated with CPI203 plus bortezomib increased the apoptosis level and decreased the proliferation rate 106 . Furthermore, CPI203 demonstrated its efficacy in pancreatic neuroendocrine tumors (PanNET) by downregulating MYC expression, producing G1 cell cycle arrest and almost completely inhibiting cell proliferation.…”

Section: Bromodomain Inhibitorsmentioning

confidence: 99%

Bromodomain inhibitors and cancer therapy: From structures to applications

2016

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Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are “writers,” “erasers,” or “readers” of histone modification marks are common. Bromodomains are “readers” that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains. In recent years, there has been increasing interest in developing small molecules that can target specific bromodomains. First, this has helped clarify biological functions of bromodomain-containing proteins. Secondly, it opens a new front for combatting cancer. In this review we will describe the structures and mechanisms associated with Bromodomain and Extra-Terminal motif (BET) inhibitors and non-BET inhibitors, their current status of development, and their promising role as anti-cancer agents.

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Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma

Cited by 42 publications

References 44 publications

BET bromodomain inhibitors synergize with ATR inhibitors in melanoma

BET bromodomain inhibitors synergize with ATR inhibitors in melanoma

Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma

Bromodomain inhibitors and cancer therapy: From structures to applications

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