Therapeutically targeting oncogenic CRCs facilitates induced differentiation of NB by RA and the BET bromodomain inhibitor.
Therapeutically targeting oncogenic CRCs facilitates induced differentiation of NB by RA and the BET bromodomain inhibitor.
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DOI：
10.1016/j.omto.2021.09.004
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发表时间：
2021-12-17
期刊：
影响因子：
--
通讯作者：
Freeman KW
中科院分区：
文献类型：
--
作者：
Alleboina S;Aljouda N;Miller M;Freeman KW
视黄酸（RA）是用于高风险神经母细胞瘤（NB）维持治疗中的癌症分化治疗的最成功的治疗剂，但有效性有限。本研究确定了一种通过BET抑制剂破坏癌细胞身份来提高疗效的策略。理论上，阻断发育的突变通过保留有助于肿瘤发生的未成熟细胞身份而引起NB。NB具有两种可互换的细胞身份，由两种不同的核心转录调控电路（CRC）维持：治疗抗性间充质/干细胞状态和增殖性肾上腺素能细胞状态。MYCN扩增是高危NB的常见突变，最近发现通过驱动肾上腺素能CRC转录因子ASCL 1的高表达来阻断分化。我们研究了破坏未成熟的CRCs是否可以促进RA诱导的分化，因为只有一部分NB患者对RA有反应。我们发现，沉默ASCL 1，肾上腺素能CRC的关键成员，或用BET抑制剂JQ 1全面破坏CRC，抑制多种CRC因子的基因表达，改善RA介导的分化。此外，JQ 1和RA协同降低NB细胞系的增殖并诱导分化。我们的研究结果支持RA和BET抑制剂作为治疗NB的联合疗法的临床前研究。尽管其有效性有限，但视黄酸是用于癌症分化治疗的最成功的治疗剂。本研究确定了一种通过使用BET布罗莫结构域抑制剂来破坏导致肿瘤异质性和致癌进展的发育不成熟癌细胞身份状态来提高其疗效的策略。
Retinoic acids (RAs) are the most successful therapeutics for cancer differentiation therapy used in high-risk neuroblastoma (NB) maintenance therapy but are limited in effectiveness. This study identifies a strategy for improving efficacy through disruption of cancer cell identity via BET inhibitors. Mutations that block development are theorized to cause NB through retention of immature cell identities contributing to oncogenesis. NB has two interchangeable cell identities, maintained by two different core transcriptional regulatory circuitries (CRCs): a therapy-resistant mesenchymal/stem cell state and a proliferative adrenergic cell state. MYCN amplification is a common mutation of high-risk NB and recently found to block differentiation by driving high expression of the adrenergic CRC transcription factor ASCL1. We investigated whether disruption of immature CRCs can promote RA-induced differentiation since only a subset of NB patients responds to RA. We found that silencing ASCL1, a critical member of the adrenergic CRC, or global disruption of CRCs with the BET inhibitor JQ1, suppresses gene expression of multiple CRC factors, improving RA-mediated differentiation. Further, JQ1 and RA synergistically decrease proliferation and induce differentiation in NB cell lines. Our findings support preclinical studies of RA and BET inhibitors as a combination therapy in treating NB. Although limited in their effectiveness, retinoic acids are the most successful therapeutics for differentiation therapy in cancer. This study identifies a strategy to improve their efficacy through use of BET bromodomain inhibitors to disrupt developmentally immature cancer cell identity states that contribute to tumor heterogeneity and oncogenic progression.
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
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8
作者：
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5.3
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