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JQ1 induces DNA damage and apoptosis, and inhibits tumor growth in a patient-derived xenograft model of cholangiocarcinoma
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2017-11-15 , DOI: 10.1158/1535-7163.mct-16-0922
Patrick L. Garcia 1 , Aubrey L. Miller 1 , Tracy L. Gamblin 1 , Leona N. Council 2, 3 , John D. Christein 4 , J. Pablo Arnoletti 5 , Marty J. Heslin 5 , Sushanth Reddy 5 , Joseph H. Richardson 5 , Xiangqin Cui 6 , Robert C.A.M. van Waardenburg 1 , James E. Bradner 7 , Eddy S. Yang 8 , Karina J. Yoon 1
Affiliation  

Cholangiocarcinoma (CCA) is a fatal disease with a 5-year survival of <30%. For a majority of patients, chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the first-line 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 antitumor 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. Mol Cancer Ther; 17(1); 107–18. ©2017 AACR.

中文翻译:

JQ1 诱导 DNA 损伤和细胞凋亡,并抑制患者来源的胆管癌异种移植模型中的肿瘤生长

胆管癌 (CCA) 是一种致命疾病,5 年生存率 <30%。对于大多数患者,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。将该药物与顺铂联合使用可将生存期延长约 3 个月,但两种方案均不会产生持久的缓解。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 患者来源的异种移植 (PDX) 模型。我们使用其中两个模型来研究溴结构域抑制剂 JQ1 的抗肿瘤功效和作用机制,JQ1 是一种尚未评估治疗 CCA 的药物。数据显示 JQ1 抑制了 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。第二种模型 (CCA1) 对 JQ1 不敏感,肿瘤进展和 c-Myc 表达不受暴露于该试剂的影响。同样对 CCA2 肿瘤具有选择性,JQ1 诱导 DNA 损伤和细胞凋亡,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。我们得出结论,BET 抑制剂如 JQ1 需要进一步研究 CCA 的治疗。摩尔癌症治疗; 17(1); 107-18。©2017 AACR。
更新日期:2017-11-15
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