Pharmaco-transcriptomic correlation analysis reveals novel responsive signatures to HDAC inhibitors and identifies Dasatinib as a synergistic interactor in small-cell lung cancer.
Pharmaco-transcriptomic correlation analysis reveals novel responsive signatures to HDAC inhibitors and identifies Dasatinib as a synergistic interactor in small-cell lung cancer.
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DOI：
10.1016/j.ebiom.2021.103457
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发表时间：
2021-07
期刊：
影响因子：
11.1
通讯作者：
Yao F
中科院分区：
文献类型：
--
作者：
Yang H;Sun B;Xu K;He Y;Zhang T;Hall SRR;Tan ST;Schmid RA;Peng RW;Hu G;Yao F
组蛋白乙酰化/去乙酰化酶修饰是研究最多的表观遗传修饰之一。组蛋白去乙酰化酶抑制剂（HDACis）在血液恶性肿瘤中显示出临床获益，但由于缺乏生物标志物驱动的分层，在实体瘤中失败。我们通过将五种泛HDACis的药物反应谱与实体癌细胞系的转录组（n=659）相关联来进行综合药物转录组学分析，以系统地鉴定与HDACis敏感性和抗性相关的可概括的基因特征。然后将建立的特征应用于鉴定对HDACis潜在敏感或耐药的癌症亚型，以及增强HDACis疗效的药物。最后，通过多个独立的药物反应数据集和实验测定来评估所建立的HDACis签名的再现性。我们成功地描绘了预测对所有五种HDACis的敏感性（含有46个基因）和抗性（含有53个基因）的可推广的基因签名，其繁殖力通过多个外部来源和独立的内部测定得到证实。使用基因特征，我们确定了低级别胶质瘤携带异柠檬酸脱氢酶1/2（IDH 1/2）突变和非YAP 1驱动的小细胞肺癌（SCLC）的子集，特别是受益于HDACis单药治疗。此外，基于耐药基因特征，我们将临床批准的达沙替尼鉴定为具有HDACi的合成致死药物，其在诱导一组SCLC的细胞凋亡和活性氧方面具有协同作用。最后，达沙替尼显著增强伏立诺他在SCLC异种移植物中的治疗功效。我们的工作建立了预测实体癌中HDACi敏感性/耐药性的强大基因特征，并揭示了联合达沙替尼/HDACi作为SCLC的合成致死性联合疗法。
Histone acetylation/deacetylase process is one of the most studied epigenetic modifications. Histone deacetylase inhibitors (HDACis) have shown clinical benefits in haematological malignancies but failed in solid tumours due to the lack of biomarker-driven stratification. We perform integrative pharmaco-transcriptomic analysis by correlating drug response profiles of five pan-HDACis with transcriptomes of solid cancer cell lines (n=659) to systematically identify generalizable gene signatures associated with HDACis sensitivity and resistance. The established signatures are then applied to identify cancer subtypes that are potentially sensitive or resistant to HDACis, and drugs that enhance the efficacy of HDACis. Finally, the reproductivity of the established HDACis signatures is evaluated by multiple independent drug response datasets and experimental assays. We successfully delineate generalizable gene signatures predicting sensitivity (containing 46 genes) and resistance (containing 53 genes) to all five HDACis, with their reproductivity confirmed by multiple external sources and independent internal assays. Using the gene signatures, we identify low-grade glioma harbouring isocitrate dehydrogenase 1/2 (IDH1/2) mutation and non-YAP1-driven subsets of small-cell lung cancer (SCLC) that particularly benefit from HDACis monotherapy. Further, based on the resistance gene signature, we identify clinically-approved Dasatinib as a synthetic lethal drug with HDACi, synergizing in inducing apoptosis and reactive oxygen species on a panel of SCLC. Finally, Dasatinib significantly enhances the therapeutic efficacy of Vorinostat in SCLC xenografts. Our work establishes robust gene signatures predicting HDACis sensitivity/resistance in solid cancer and uncovers combined Dasatinib/HDACi as a synthetic lethal combination therapy for SCLC.
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影响因子：
64.5
作者：
Basu A;Bodycombe NE;Cheah JH;Price EV;Liu K;Schaefer GI;Ebright RY;Stewart ML;Ito D;Wang S;Bracha AL;Liefeld T;Wawer M;Gilbert JC;Wilson AJ;Stransky N;Kryukov GV;Dancik V;Barretina J;Garraway LA;Hon CS;Munoz B;Bittker JA;Stockwell BR;Khabele D;Stern AM;Clemons PA;Shamji AF;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
28.2
作者：
Jia D;Augert A;Kim DW;Eastwood E;Wu N;Ibrahim AH;Kim KB;Dunn CT;Pillai SPS;Gazdar AF;Bolouri H;Park KS;MacPherson D
通讯作者：
MacPherson D
影响因子：
11.5
作者：
Fantin, Valeria R.;Richon, Victoria M.
通讯作者：
Richon, Victoria M.
影响因子：
5.7
作者：
Bruzzese, Francesca;Rocco, Monia;Budillon, Alfredo
通讯作者：
Budillon, Alfredo
影响因子：
7.3
作者：
Ho, Terence C. S.;Chan, Alex H. Y.;Ganesan, A.
通讯作者：
Ganesan, A.