title: High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.
abstract: Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo.
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Channing
authors.identifier: http://orcid.org/0000-0002-3231-2565
authors.initials: C
authors.lastname: Yu
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Aristotle M
authors.initials: AM
authors.lastname: Mannan
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Griselda Metta
authors.initials: GM
authors.lastname: Yvone
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Ross
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Marton
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Taylor
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Crenshaw
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Joshua Z
authors.initials: JZ
authors.lastname: Gould
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Pablo
authors.identifier: http://orcid.org/0000-0002-9360-4668
authors.initials: P
authors.lastname: Tamayo
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weir
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Aviad
authors.identifier: http://orcid.org/0000-0002-3797-1877
authors.initials: A
authors.lastname: Tsherniak
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Bang
authors.initials: B
authors.lastname: Wong
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Palmer
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Foley
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Harvard University, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058893:DNA Barcoding, Taxonomic / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D060005:Genotyping Techniques / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000145:classification* / Q000235:genetics*