title: A network-based phenotype mapping approach to identify genes that modulate drug response phenotypes.
abstract: To better address the problem of drug resistance during cancer chemotherapy and explore the possibility of manipulating drug response phenotypes, we developed a network-based phenotype mapping approach (P-Map) to identify gene candidates that upon perturbed can alter sensitivity to drugs. We used basal transcriptomics data from a panel of human lymphoblastoid cell lines (LCL) to infer drug response networks (DRNs) that are responsible for conferring response phenotypes for anthracycline and taxane, two common anticancer agents use in clinics. We further tested selected gene candidates that interact with phenotypic differentially expressed genes (PDEGs), which are up-regulated genes in LCL for a given class of drug response phenotype in triple-negative breast cancer (TNBC) cells. Our results indicate that it is possible to manipulate a drug response phenotype, from resistant to sensitive or vice versa, by perturbing gene candidates in DRNs and suggest plausible mechanisms regulating directionality of drug response sensitivity. More important, the current work highlights a new way to formulate systems-based therapeutic design: supplementing therapeutics that aim to target disease culprits with phenotypic modulators capable of altering DRN properties with the goal to re-sensitize resistant phenotypes.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Junmei
authors.initials: J
authors.lastname: Cairns
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Choong Yong
authors.initials: CY
authors.lastname: Ung
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Edroaldo Lummertz
authors.initials: EL
authors.lastname: da Rocha
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Correia
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Weinshilboum
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000465:Algorithms; D018943:Anthracyclines / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity*; D001952:Bridged-Ring Compounds / Q000633:toxicity; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006801:Humans; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism; D043823:Taxoids / Q000633:toxicity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018943:Anthracyclines; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; C489989:EPS8 protein, human; C508590:IL1R1 protein, human; D034741:RNA, Small Interfering; D053573:Receptors, Interleukin-1 Type I; D043823:Taxoids; C080625:taxane; C000595354:NME7 protein, human; D009701:Nucleoside-Diphosphate Kinase