JQ1 Induces DNA Damage and Apoptosis, and Inhibits Tumor Growth in a Patient-Derived Xenograft Model of Cholangiocarcinoma.
JQ1 Induces DNA Damage and Apoptosis, and Inhibits Tumor Growth in a Patient-Derived Xenograft Model of Cholangiocarcinoma.
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DOI：
10.1158/1535-7163.mct-16-0922
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发表时间：
2018-01
影响因子：
5.7
通讯作者：
Yoon KJ
中科院分区：
文献类型：
--
作者：
Garcia PL;Miller AL;Gamblin TL;Council LN;Christein JD;Arnoletti JP;Heslin MJ;Reddy S;Richardson JH;Cui X;van Waardenburg RCAM;Bradner JE;Yang ES;Yoon KJ
胆管癌（CCA）是一种致命的疾病，五年生存率<30%。对于大多数患者来说，化疗是唯一的治疗选择，几乎所有患者都会复发。吉西他滨是治疗CCA的一线药物。接受吉西他滨单药治疗的患者存活约8个月。将这种药物与顺铂联合使用可使生存期延长约3个月，但两种方案均不能产生持久缓解。这种疾病的分子病因学知之甚少。为了促进CCA的分子表征和有效疗法的开发，我们建立了一组CCA的患者来源的异种移植物（PDX）模型。我们使用其中两种模型来研究布罗莫结构域抑制剂JQ1的抗肿瘤功效和作用机制，JQ1是一种尚未评估用于治疗CCA的药剂。数据显示JQ1抑制CCA PDX模型CCA2的生长，并证明生长抑制伴随着c-Myc蛋白表达的抑制。第二个模型（CCA1）是JQ1不敏感的，肿瘤进展和c-Myc表达不受暴露于这种药物的影响。JQ1对CCA2肿瘤也有选择性，它诱导DNA损伤和凋亡，并下调调节细胞周期进程和DNA修复的多个c-Myc转录靶点。这些发现表明，c-Myc抑制及其几个转录靶点可能有助于JQ1在这种肿瘤类型中的作用机制。我们的结论是BET抑制剂，如JQ1值得进一步调查CCA的治疗。
Cholangiocarcinoma (CCA) is a fatal disease with a five-year survival of <30%. For a majority of patients chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the frontline agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ~8 months. Combining this agent with cisplatin increases survival by ~3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the anti-tumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2, and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis, and downregulated multiple c-Myc transcriptional targets that regulate cell cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA.