Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Department of Pathology and ARUP Laboratories, University of Utah, Salt Lake City, Utah.
Mol Cancer Ther. 2019 Jan;18(1):185-195. doi: 10.1158/1535-7163.MCT-17-0957. Epub 2018 Oct 9.
Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma; the genomic basis for clinical response is not known. In two separate phase I clinical trials testing pharmacokinetic aspects of HDAC inhibitors in advanced solid tumors, we identified one patient with advanced urothelial carcinoma who had a complete response to belinostat, and one patient with advanced urothelial carcinoma who had a partial response to panobinostat. The archived tumors of the responders were genomically characterized in comparison to others with urothelial carcinoma on the trials. Urothelial carcinoma cell lines treated with panobinostat and belinostat were studied to elucidate the mechanisms of benefit. Notably, the urothelial carcinoma tumors that responded to HDAC inhibition had mutations. mutations were also noted in the tumors of three patients who had stable disease as their best response to HDAC inhibition. Corroborating the basis of sensitivity, transcriptional profiling of platinum-resistant -mutated HT1197 cells treated with panobinostat reveals negative enrichment for both cyto-proliferative (MYC and E2F targets) and DNA repair gene sets, and positive enrichment for TP53 and inflammatory gene sets. Our study identifies loss as a basis for clinical response to pan HDAC inhibition and offers avenues for potential rational therapeutic combinations with HDAC inhibitors in advanced urothelial carcinoma.
组蛋白去乙酰化酶（HDAC）抑制在尿路上皮癌中具有零星的临床疗效；其临床反应的基因组基础尚不清楚。在两项分别测试 HDAC 抑制剂在晚期实体瘤中药代动力学方面的 I 期临床试验中，我们发现一名晚期尿路上皮癌患者对贝林司他有完全反应，一名晚期尿路上皮癌患者对帕比司他有部分反应。与试验中的其他尿路上皮癌患者相比，对有反应者的存档肿瘤进行了基因组特征分析。研究了用帕比司他和贝林司他处理的尿路上皮癌细胞系，以阐明获益的机制。值得注意的是，对 HDAC 抑制有反应的尿路上皮癌肿瘤有 突变。在对 HDAC 抑制有稳定疾病反应的最佳反应的三名患者的肿瘤中也观察到了 突变。与敏感性的基础相一致，用帕比司他处理的铂耐药 - 突变 HT1197 细胞的转录谱分析显示，细胞增殖（MYC 和 E2F 靶标）和 DNA 修复基因集呈负富集，而 TP53 和炎症基因集呈正富集。我们的研究确定了 缺失是对 pan HDAC 抑制有临床反应的基础，并为晚期尿路上皮癌中与 HDAC 抑制剂联合应用的潜在合理治疗组合提供了途径。
