Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer
Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer
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DOI：
10.1038/s41598-019-40518-5
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发表时间：
2019-03-07
影响因子：
4.6
通讯作者：
Alumkal, Joshi J.
中科院分区：
文献类型：
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作者：
Coleman, Daniel J.;Gao, Lina;Alumkal, Joshi J.
BET布罗莫结构域蛋白BRD 4是调节转录的染色质阅读器，包括在癌症中。具体地，在前列腺癌中，BET布罗莫结构域抑制的抗肿瘤活性主要与雄激素受体（AR）功能的抑制有关。MYC是一种在多种癌症类型中被充分描述的BRD 4靶基因，先前的工作表明MYC在促进前列腺癌细胞存活方面起着重要作用。重要的是，几项BET溴结构域临床试验正在进行中，包括前列腺癌。然而，关于反应的药效学标志物或新生耐药介质的信息有限。使用一组前列腺癌细胞系，我们证明了MYC抑制-而不是AR抑制-是BET布罗莫结构域抑制剂敏感性的关键决定因素。重要的是，我们确定了BRD 4在大多数抗性细胞系中对MYC表达起抑制作用，并且MYC RNAi + BET布罗莫结构域抑制导致大多数抗性细胞系中的附加抗肿瘤活性。我们的研究结果表明，MYC抑制是BET溴结构域抑制剂反应的重要药效学标志物，并表明靶向MYC可能是克服前列腺癌中从头BET溴结构域抑制剂耐药性的有希望的治疗策略。
The BET bromodomain protein BRD4 is a chromatin reader that regulates transcription, including in cancer. In prostate cancer, specifically, the anti-tumor activity of BET bromodomain inhibition has been principally linked to suppression of androgen receptor (AR) function. MYC is a well-described BRD4 target gene in multiple cancer types, and prior work demonstrates that MYC plays an important role in promoting prostate cancer cell survival. Importantly, several BET bromodomain clinical trials are ongoing, including in prostate cancer. However, there is limited information about pharmacodynamic markers of response or mediators of de novo resistance. Using a panel of prostate cancer cell lines, we demonstrated that MYC suppression-rather than AR suppression-is a key determinant of BET bromodomain inhibitor sensitivity. Importantly, we determined that BRD4 was dispensable for MYC expression in the most resistant cell lines and that MYC RNAi + BET bromodomain inhibition led to additive anti-tumor activity in the most resistant cell lines. Our findings demonstrate that MYC suppression is an important pharmacodynamic marker of BET bromodomain inhibitor response and suggest that targeting MYC may be a promising therapeutic strategy to overcome de novo BET bromodomain inhibitor resistance in prostate cancer.