Perturbation-informed signatures from crosswise integration of transcriptome and chromatin accessibility analyses predict susceptibility to candidate anticancer drugs [ATAC-Seq]. Perturbation-informed signatures from crosswise integration of transcriptome and chromatin accessibility analyses predict susceptibility to candidate anticancer drugs [ATAC-Seq]

Despite the tremendous advances in the use of omic-based technologies to serve the new paradigm of precision medicine, efforts are still required to expedite their routine use in drug discovery. In this work, we present a case study describing the use of multi-omics to push the development of 3-chloropiperidines (3-CePs), a new class of potential anticancer DNA alkylating agents. The combined analyses of transcriptome and chromatin accessibility efficiently identified proteostasis and DNA repair unbalances as the mechanisms underlying the tropism of 3-CePs against a pancreatic adenocarcinoma cell line. Further on, we implemented a new versatile strategy for the integration of RNA-seq and ATAC-seq information, which could be easily exported to accelerate and extend the separate analyses of omic layers. In addition, this platform offered a new anchor for the construction of a perturbation-informed basal signature able to efficiently predict cell lines sensitivity to 3-CePs and to further direct their development against specific tumor types. Overall, this approach offered a clinically-applicable pipeline to support both the early phases of drug discovery and the correct positioning of therapeutics in the medical practice. Overall design: Chromatin accessibility profile (ATAC) of BxPC-3 and HCT-15 treated with 2 compounds of the 3-chloropiperidines class. The analysis was performed at 2 time-points including untreated control to investigate the dynamic effect of the new molecules.

尽管基于组学（omic-based）的技术在支撑精准医学新范式领域已取得长足进展，但仍需投入更多努力以加速其在药物发现中的常规应用。本研究报道了一项案例研究，阐述了多组学（multi-omics）技术在推动3-氯哌啶类化合物（3-chloropiperidines, 3-CePs）开发中的应用——该类化合物是一类新型潜在抗癌DNA烷化剂（DNA alkylating agents）。通过转录组（transcriptome）与染色质开放性（chromatin accessibility）的联合分析，研究团队高效鉴定出蛋白稳态（proteostasis）与DNA修复失衡是3-CePs针对胰腺腺癌细胞系（pancreatic adenocarcinoma cell line）产生靶向选择性的核心机制。后续本研究开发了一种全新的通用策略，用于整合RNA测序（RNA-seq）与转座酶可及性测序（ATAC-seq）数据，该策略可便捷导出，以加速并拓展组学层面的独立分析。此外，该平台为构建基于扰动信息的基础特征标签提供了全新锚点，该标签可高效预测细胞系对3-CePs的敏感性，并进一步指导化合物针对特定肿瘤类型的开发。总体而言，本方法提供了一条可临床应用的分析流程，可同时支撑药物发现的早期阶段与治疗药物在临床实践中的合理定位。
整体实验设计：对经3-氯哌啶类化合物（3-chloropiperidines, 3-CePs）中2种化合物处理的BxPC-3与HCT-15细胞系开展染色质开放性（ATAC）测序分析。实验设置2个时间节点，并包含未处理对照组，以探究新型化合物的动态作用效应。