Abstract:
:Anaplastic thyroid cancer (ATC) is an aggressive malignancy with limited treatment options. We explored novel treatment modalities by targeting epigenetic modifications using inhibitors of BET (e.g. BRD4) activity. We evaluated the efficacy in the treatment of ATC of a novel BET inhibitor, PLX51107 (PLX), currently in clinical trials for other solid tumors and hematologic malignancies, alone or combined with a MEK inhibitor, PD0325901(PD). To elucidate the effects of these inhibitors on growth of ATC, we treated ATC cells derived from patient tumors (THJ-11T and THJ-16T cells) and mouse xenograft tumors with inhibitors. We found PLX and PD inhibitors singly inhibited proliferation of both human ATC cells lines, but together exhibited stronger inhibition of proliferation. In mouse xenografts, the combination treatment almost totally blocked growth in xenograft tumors derived from both ATC cells. PD effectively attenuated MEK-ERK signaling, which was further enhanced by PLX in the combined treatment in cultured cells and tumors. Importantly, the combination of PLX and PD acted synergistically to suppress MYC transcription to increase p27 in decreasing tumor cell proliferation. PLX and PD cooperated to upregulate pro-apoptotic proteins to promote apoptosis. These two inhibitors converged to reduce the binding of BRD4 to the MYC promoter to suppress the MYC expression. These findings indicate that combined treatment of BET and MEK-ERK inhibitors was more effective to treat ATC than single targeted treatment. Synergistic suppression of MYC transcription via collaborative actions on chromatin modifications suggested that targeting epigenetic modifications could provide novel treatment opportunities for ATC.
journal_name
Endocr Relat Cancerjournal_title
Endocrine-related cancerauthors
Zhu X,Park S,Lee WK,Cheng SYdoi
10.1530/ERC-19-0107subject
Has Abstractpub_date
2019-09-01 00:00:00pages
739-750issue
9eissn
1351-0088issn
1479-6821pii
ERC-19-0107.R1journal_volume
26pub_type
杂志文章abstract::The aim of this study was to explore the pharmacological response to 4-hydroxy-tamoxifen (OH-Tam) and to estradiol (E2) in three cell lines: MVLN, a human breast carcinoma cell line derived from MCF-7, and two MVLN-derived OH-Tam-resistant (OTR) cell lines, called CL6.8 and CL6.32. The OH-Tam response in the OTR cells...
journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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pub_type: 杂志文章
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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pub_type: 杂志文章,随机对照试验
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更新日期:2013-02-18 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
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更新日期:2018-03-01 00:00:00
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journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
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