A community challenge for a pancancer drug mechanism of action inference from perturbational profile data

Cell Rep Med. 2022 Jan 18;3(1):100492. doi: 10.1016/j.xcrm.2021.100492.

Abstract

The Columbia Cancer Target Discovery and Development (CTD2) Center is developing PANACEA, a resource comprising dose-responses and RNA sequencing (RNA-seq) profiles of 25 cell lines perturbed with ∼400 clinical oncology drugs, to study a tumor-specific drug mechanism of action. Here, this resource serves as the basis for a DREAM Challenge assessing the accuracy and sensitivity of computational algorithms for de novo drug polypharmacology predictions. Dose-response and perturbational profiles for 32 kinase inhibitors are provided to 21 teams who are blind to the identity of the compounds. The teams are asked to predict high-affinity binding targets of each compound among ∼1,300 targets cataloged in DrugBank. The best performing methods leverage gene expression profile similarity analysis as well as deep-learning methodologies trained on individual datasets. This study lays the foundation for future integrative analyses of pharmacogenomic data, reconciliation of polypharmacology effects in different tumor contexts, and insights into network-based assessments of drug mechanisms of action.

Keywords: DREAM challenge; community challenge; pharmacogenomics; polypharmacology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasms / drug therapy*
  • Neural Networks, Computer
  • Polypharmacology*
  • Protein Kinases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription, Genetic

Substances

  • RNA, Messenger
  • Protein Kinases