title: Correlating chemical sensitivity and basal gene expression reveals mechanism of action.
abstract: Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown. To test this idea, we correlated the sensitivity patterns of 481 compounds with ∼19,000 basal transcript levels across 823 different human cancer cell lines and identified selective outlier transcripts. This process yielded many novel mechanistic insights, including the identification of activation mechanisms, cellular transporters and direct protein targets. We found that ML239, originally identified in a phenotypic screen for selective cytotoxicity in breast cancer stem-like cells, most likely acts through activation of fatty acid desaturase 2 (FADS2). These data and analytical tools are available to the research community through the Cancer Therapeutics Response Portal.
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Rees
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.|Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden (B.S.L); Koch Institute for Cancer Research at MIT, Cambridge, Massachusetts, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Novartis Institutes for Biomedical Research, Emeryville, California, USA; Pfizer, Cambridge, Massachusetts, USA; University of California San Diego School of Medicine, La Jolla, California, USA; ImmunoGen, Waltham, Massachusetts, USA.
authors.forename: Brinton
authors.identifier: http://orcid.org/0000-0001-8658-5967
authors.initials: B
authors.lastname: Seashore-Ludlow
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.|Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden (B.S.L); Koch Institute for Cancer Research at MIT, Cambridge, Massachusetts, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Novartis Institutes for Biomedical Research, Emeryville, California, USA; Pfizer, Cambridge, Massachusetts, USA; University of California San Diego School of Medicine, La Jolla, California, USA; ImmunoGen, Waltham, Massachusetts, USA.
authors.forename: Jaime H
authors.initials: JH
authors.lastname: Cheah
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.|Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden (B.S.L); Koch Institute for Cancer Research at MIT, Cambridge, Massachusetts, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Novartis Institutes for Biomedical Research, Emeryville, California, USA; Pfizer, Cambridge, Massachusetts, USA; University of California San Diego School of Medicine, La Jolla, California, USA; ImmunoGen, Waltham, Massachusetts, USA.
authors.forename: Drew J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.|Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden (B.S.L); Koch Institute for Cancer Research at MIT, Cambridge, Massachusetts, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Novartis Institutes for Biomedical Research, Emeryville, California, USA; Pfizer, Cambridge, Massachusetts, USA; University of California San Diego School of Medicine, La Jolla, California, USA; ImmunoGen, Waltham, Massachusetts, USA.
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Price
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Shubhroz
authors.initials: S
authors.lastname: Gill
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Javaid
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Coletti
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Jones
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.|Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden (B.S.L); Koch Institute for Cancer Research at MIT, Cambridge, Massachusetts, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Novartis Institutes for Biomedical Research, Emeryville, California, USA; Pfizer, Cambridge, Massachusetts, USA; University of California San Diego School of Medicine, La Jolla, California, USA; ImmunoGen, Waltham, Massachusetts, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Bodycombe
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.|Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden (B.S.L); Koch Institute for Cancer Research at MIT, Cambridge, Massachusetts, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Novartis Institutes for Biomedical Research, Emeryville, California, USA; Pfizer, Cambridge, Massachusetts, USA; University of California San Diego School of Medicine, La Jolla, California, USA; ImmunoGen, Waltham, Massachusetts, USA.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Soule
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Benjamin
authors.identifier: http://orcid.org/0000-0002-0960-6119
authors.initials: B
authors.lastname: Alexander
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Ava
authors.initials: A
authors.lastname: Li
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Philip
authors.identifier: http://orcid.org/0000-0002-2633-1081
authors.initials: P
authors.lastname: Montgomery
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Joanne D
authors.initials: JD
authors.lastname: Kotz
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: C Suk-Yee
authors.initials: CS
authors.lastname: Hon
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.|Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden (B.S.L); Koch Institute for Cancer Research at MIT, Cambridge, Massachusetts, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Novartis Institutes for Biomedical Research, Emeryville, California, USA; Pfizer, Cambridge, Massachusetts, USA; University of California San Diego School of Medicine, La Jolla, California, USA; ImmunoGen, Waltham, Massachusetts, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Liefeld
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Vlado
authors.initials: V
authors.lastname: Dančík
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Clary B
authors.identifier: http://orcid.org/0000-0001-8259-9245
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Joshua A
authors.identifier: http://orcid.org/0000-0002-4166-0828
authors.initials: JA
authors.lastname: Bittker
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.|Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden (B.S.L); Koch Institute for Cancer Research at MIT, Cambridge, Massachusetts, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Novartis Institutes for Biomedical Research, Emeryville, California, USA; Pfizer, Cambridge, Massachusetts, USA; University of California San Diego School of Medicine, La Jolla, California, USA; ImmunoGen, Waltham, Massachusetts, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Palmer
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Stuart L
authors.identifier: http://orcid.org/0000-0003-1922-7558
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000348:Aflatoxins / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D003198:Computer Simulation; D016503:Drug Delivery Systems; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D025341:Principal Component Analysis; D060888:Real-Time Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D000348:Aflatoxins; D054852:Small Molecule Libraries; C558970:austocystin D