title: Systematic identification of genomic markers of drug sensitivity in cancer cells.
abstract: Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Garnett
authors.forename: Elena J
authors.initials: EJ
authors.lastname: Edelman
authors.forename: Sonja J
authors.initials: SJ
authors.lastname: Heidorn
authors.forename: Chris D
authors.initials: CD
authors.lastname: Greenman
authors.forename: Anahita
authors.initials: A
authors.lastname: Dastur
authors.forename: King Wai
authors.initials: KW
authors.lastname: Lau
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.forename: I Richard
authors.initials: IR
authors.lastname: Thompson
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.forename: Jorge
authors.initials: J
authors.lastname: Soares
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Francesco
authors.initials: F
authors.lastname: Iorio
authors.forename: Didier
authors.initials: D
authors.lastname: Surdez
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Milano
authors.forename: Graham R
authors.initials: GR
authors.lastname: Bignell
authors.forename: Ah T
authors.initials: AT
authors.lastname: Tam
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Stevenson
authors.forename: Syd
authors.initials: S
authors.lastname: Barthorpe
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Lutz
authors.forename: Fiona
authors.initials: F
authors.lastname: Kogera
authors.forename: Karl
authors.initials: K
authors.lastname: Lawrence
authors.forename: Anne
authors.initials: A
authors.lastname: McLaren-Douglas
authors.forename: Xeni
authors.initials: X
authors.lastname: Mitropoulos
authors.forename: Tatiana
authors.initials: T
authors.lastname: Mironenko
authors.forename: Helen
authors.initials: H
authors.lastname: Thi
authors.forename: Laura
authors.initials: L
authors.lastname: Richardson
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhou
authors.forename: Frances
authors.initials: F
authors.lastname: Jewitt
authors.forename: Tinghu
authors.initials: T
authors.lastname: Zhang
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Brien
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Boisvert
authors.forename: Stacey
authors.initials: S
authors.lastname: Price
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.forename: Wanjuan
authors.initials: W
authors.lastname: Yang
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Adam
authors.initials: A
authors.lastname: Butler
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.forename: Ivan
authors.initials: I
authors.lastname: Stamenkovic
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Sreenath V
authors.initials: SV
authors.lastname: Sharma
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Julio
authors.initials: J
authors.lastname: Saez-Rodriguez
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010597:Pharmacogenetics; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics; D034802:RNA-Binding Protein EWS / Q000235:genetics; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics / Q000473:pathology
chemical_list: C106031:EWS-FLI fusion protein; D005819:Genetic Markers; D007211:Indoles; D015514:Oncogene Proteins, Fusion; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; C531549:rucaparib; C531550:olaparib