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.