title: Predicting chemotherapeutic drug combinations through gene network profiling.
abstract: Contemporary chemotherapeutic treatments incorporate the use of several agents in combination. However, selecting the most appropriate drugs for such therapy is not necessarily an easy or straightforward task. Here, we describe a targeted approach that can facilitate the reliable selection of chemotherapeutic drug combinations through the interrogation of drug-resistance gene networks. Our method employed single-cell eukaryote fission yeast (Schizosaccharomyces pombe) as a model of proliferating cells to delineate a drug resistance gene network using a synthetic lethality workflow. Using the results of a previous unbiased screen, we assessed the genetic overlap of doxorubicin with six other drugs harboring varied mechanisms of action. Using this fission yeast model, drug-specific ontological sub-classifications were identified through the computation of relative hypersensitivities. We found that human gastric adenocarcinoma cells can be sensitized to doxorubicin by concomitant treatment with cisplatin, an intra-DNA strand crosslinking agent, and suberoylanilide hydroxamic acid, a histone deacetylase inhibitor. Our findings point to the utility of fission yeast as a model and the differential targeting of a conserved gene interaction network when screening for successful chemotherapeutic drug combinations for human cells.
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.|National University Health System (NUHS), Singapore.
authors.forename: Thi Thuy Trang
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.|Department of Chemistry, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Jacqueline Kia Kee
authors.initials: JK
authors.lastname: Chua
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.|National University Health System (NUHS), Singapore.
authors.forename: Kwi Shan
authors.initials: KS
authors.lastname: Seah
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Changi General Hospital, Ministry of Health, Singapore.
authors.forename: Seok Hwee
authors.initials: SH
authors.lastname: Koo
authors.affiliation: National University Health System (NUHS), Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jie Yin
authors.initials: JY
authors.lastname: Yee
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Eugene Guorong
authors.initials: EG
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.|National University Health System (NUHS), Singapore.
authors.forename: Kim Kiat
authors.initials: KK
authors.lastname: Lim
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.
authors.forename: Shermaine Yu Wen
authors.initials: SY
authors.lastname: Pang
authors.affiliation: School of Chemical and Life Sciences, Singapore Polytechnic, Singapore.
authors.forename: Audrey
authors.initials: A
authors.lastname: Yuen
authors.affiliation: Department of Mathematics, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Louxin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.|Department of Chemistry, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Brian
authors.initials: B
authors.lastname: Dymock
authors.affiliation: National University Health System (NUHS), Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Edmund Jon Deoon
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.|National University Health System (NUHS), Singapore.|NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), Life Sciences Institute, National University of Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
authors.forename: Ee Sin
authors.initials: ES
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004338:Drug Combinations; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006801:Humans; D009154:Mutation; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D004317:Doxorubicin