Transcriptional regulators (TRs) participate in essential processes in cancer pathogenesis and are critical therapeutic targets. Identification of drug response-related TRs from cell line-based compound screening data is often challenging due to low mRNA abundance of TRs, protein modifications, and other confounders (CFs). In this study, we developed a regression-based pharmacogenomic and ChIP-seq data integration method (RePhine) to infer the impact of TRs on drug response through integrative analyses of pharmacogenomic and ChIP-seq data. RePhine was evaluated in simulation and pharmacogenomic data and was applied to pan-cancer datasets with the goal of biological discovery. In simulation data with added noises or CFs and in pharmacogenomic data, RePhine demonstrated an improved performance in comparison with three commonly used methods (including Pearson correlation analysis, logistic regression model, and gene set enrichment analysis). Utilizing RePhine and Cancer Cell Line Encyclopedia data, we observed that RePhine-derived TR signatures could effectively cluster drugs with different mechanisms of action. RePhine predicted that loss-of-function of EZH2/PRC2 reduces cancer cell sensitivity toward the BRAF inhibitor PLX4720. Experimental validation confirmed that pharmacological EZH2 inhibition increases the resistance of cancer cells to PLX4720 treatment. Our results support that RePhine is a useful tool for inferring drug response-related TRs and for potential therapeutic applications. The source code for RePhine is freely available at https://github.com/coexps/RePhine.

转录调节因子(TR) 参与癌症发病机制的基本过程，是关键的治疗靶点。由于 TRs、蛋白质修饰和其他混杂因素 (CF) 的低 mRNA 丰度，从基于细胞系的化合物筛选数据中识别药物反应相关的 TRs 通常具有挑战性。在这项研究中，我们开发了一种基于回归的药物基因组和ChIP-seq数据整合方法 ( RePhine )，通过药物基因组和 ChIP-seq 数据的综合分析来推断 TRs 对药物反应的影响。RePhine在模拟和药物基因组数据中进行了评估，并将其应用于泛癌数据集，以进行生物学发现。在添加噪声或 CF 的模拟数据和药物基因组数据中，与三种常用方法（包括 Pearson 相关分析、逻辑回归模型和基因集富集分析）相比， RePhine表现出改进的性能。利用RePhine和 Cancer Cell Line Encyclopedia 数据，我们观察到RePhine衍生的 TR 特征可以有效地将具有不同作用机制的药物聚集在一起。RePhine预测 EZH2/PRC2 的功能丧失会降低癌细胞对 BRAF 抑制剂 PLX4720 的敏感性。实验验证证实，药理学 EZH2 抑制增加了癌细胞对 PLX4720 治疗的抵抗力。我们的结果支持RePhine是推断药物反应相关 TRs 和潜在治疗应用的有用工具。RePhine的源代码可在 https://github.com/coexps/RePhine 免费获得。