title: Uncovering scaling laws to infer multidrug response of resistant microbes and cancer cells.
abstract: Drug resistance in bacterial infections and cancers constitutes a major threat to human health. Treatments often include several interacting drugs, but even potent therapies can become ineffective in resistant mutants. Here, we simplify the picture of drug resistance by identifying scaling laws that unify the multidrug responses of drug-sensitive and -resistant cells. On the basis of these scaling relationships, we are able to infer the two-drug response of resistant mutants in previously unsampled regions of dosage space in clinically relevant microbes such as E. coli, E. faecalis, S. aureus, and S. cerevisiae as well as human non-small-cell lung cancer, melanoma, and breast cancer stem cells. Importantly, we find that scaling relations also apply across evolutionarily close strains. Finally, scaling allows one to rapidly identify new drug combinations and predict potent dosage regimes for targeting resistant mutants without any prior mechanistic knowledge about the specific resistance mechanism.
authors.affiliation: FAS Center for Systems Biology, Department of Molecular and Cellular Biology, School of Engineering and Applied Sciences, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Wood
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Kris C
authors.initials: KC
authors.lastname: Wood
authors.affiliation: FAS Center for Systems Biology, Department of Molecular and Cellular Biology, School of Engineering and Applied Sciences, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishida
authors.affiliation: FAS Center for Systems Biology, Department of Molecular and Cellular Biology, School of Engineering and Applied Sciences, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA. Electronic address: cluzel@mcb.harvard.edu.
authors.forename: Philippe
authors.initials: P
authors.lastname: Cluzel
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology*; D018432:Drug Resistance, Multiple; D024901:Drug Resistance, Multiple, Bacterial; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009181:Mycoses / Q000188:drug therapy* / Q000382:microbiology*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents