title: A Semi-Supervised Approach for Refining Transcriptional Signatures of Drug Response and Repositioning Predictions.
abstract: We present a novel strategy to identify drug-repositioning opportunities. The starting point of our method is the generation of a signature summarising the consensual transcriptional response of multiple human cell lines to a compound of interest (namely the seed compound). This signature can be derived from data in existing databases, such as the connectivity-map, and it is used at first instance to query a network interlinking all the connectivity-map compounds, based on the similarity of their transcriptional responses. This provides a drug neighbourhood, composed of compounds predicted to share some effects with the seed one. The original signature is then refined by systematically reducing its overlap with the transcriptional responses induced by drugs in this neighbourhood that are known to share a secondary effect with the seed compound. Finally, the drug network is queried again with the resulting refined signatures and the whole process is carried on for a number of iterations. Drugs in the final refined neighbourhood are then predicted to exert the principal mode of action of the seed compound. We illustrate our approach using paclitaxel (a microtubule stabilising agent) as seed compound. Our method predicts that glipizide and splitomicin perturb microtubule function in human cells: a result that could not be obtained through standard signature matching methods. In agreement, we find that glipizide and splitomicin reduce interphase microtubule growth rates and transiently increase the percentage of mitotic cells-consistent with our prediction. Finally, we validated the refined signatures of paclitaxel response by mining a large drug screening dataset, showing that human cancer cell lines whose basal transcriptional profile is anti-correlated to them are significantly more sensitive to paclitaxel and docetaxel.
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics institute, Wellcome Trust Genome Campus, CB10 1SD, Cambridge, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iorio
authors.affiliation: Department of Genetics-University of Cambridge, Downing Street, CB2 3EH, Cambridge, United Kingdom.
authors.forename: Roshan L
authors.initials: RL
authors.lastname: Shrestha
authors.affiliation: Department of Genetics-University of Cambridge, Downing Street, CB2 3EH, Cambridge, United Kingdom.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levin
authors.affiliation: Department of Genetics-University of Cambridge, Downing Street, CB2 3EH, Cambridge, United Kingdom.
authors.forename: Viviane
authors.initials: V
authors.lastname: Boilot
authors.affiliation: Cancer genome project-Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, CB10 1SD, Cambridge, United Kingdom.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Garnett
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics institute, Wellcome Trust Genome Campus, CB10 1SD, Cambridge, United Kingdom; RWTH-Aachen University Hospital, Templergraben 55, 52062, Aachen, Germany.
authors.forename: Julio
authors.initials: J
authors.lastname: Saez-Rodriguez
authors.affiliation: Department of Genetics-University of Cambridge, Downing Street, CB2 3EH, Cambridge, United Kingdom.
authors.forename: Viji M
authors.initials: VM
authors.lastname: Draviam
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D058492:Drug Repositioning; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents