Histone Deacetylase Inhibition Has Targeted Clinical Benefit in ARID1A-Mutated Advanced Urothelial Carcinoma.
Histone Deacetylase Inhibition Has Targeted Clinical Benefit in ARID1A-Mutated Advanced Urothelial Carcinoma.
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DOI：
10.1158/1535-7163.mct-17-0957
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发表时间：
2019-01
影响因子：
5.7
通讯作者：
Sharma S
中科院分区：
文献类型：
--
作者：
Gupta S;Albertson DJ;Parnell TJ;Butterfield A;Weston A;Pappas LM;Dalley B;O'Shea JM;Lowrance WT;Cairns BR;Schiffman JD;Sharma S
组蛋白去乙酰化酶（HDAC）抑制剂在尿路上皮癌（UC）中具有零星的临床疗效;临床反应的基因组基础尚不清楚。在两项单独的I期临床试验中，测试了HDAC抑制剂在晚期实体瘤中的药代动力学方面，我们确定了一名晚期UC患者对贝利司他有完全反应（CR），一名晚期UC患者对帕比司他有部分反应（PR）。与试验中的其他UC患者相比，对缓解者的存档肿瘤进行基因组学表征。研究用帕比司他和贝利司他处理的UC细胞系以阐明益处的机制。值得注意的是，对HDAC抑制有反应的UC肿瘤具有ARID 1A突变。ARID 1A突变也出现在3名患者的肿瘤中，这些患者的病情稳定，是对HDAC抑制的最佳反应。用帕比司他处理的铂抗性ARID 1A突变的HT 1197细胞的转录谱分析证实了敏感性的基础，揭示了细胞增殖（MYC和E2 F靶标）和DNA修复基因集的负富集，以及TP 53和炎性基因集的正富集。我们的研究将ARID 1A缺失确定为对泛HDAC抑制的临床反应的基础，并为晚期UC中HDAC抑制剂的潜在合理治疗组合提供了途径。
Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma (UC); 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 UC who had a complete response (CR) to belinostat, and one patient with advanced UC who had a partial response (PR) to panobinostat. The archived tumors of the responders were genomically characterized in comparison to others with UC on the trials. UC cell lines treated with panobinostat and belinostat were studied to elucidate the mechanisms of benefit. Notably, the UC tumors that responded to HDAC inhibition had ARID1A mutations. ARID1A 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 ARID1A-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 ARID1A loss as a basis for clinical response to pan HDAC inhibition and offers avenues for potential rational therapeutic combinations with HDAC inhibitors in advanced UC.