title: An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules.
abstract: The high rate of clinical response to protein-kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell line (CCL) profiling to identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: (1) associate with specific cancer-genomic alterations and (2) can be targeted by small molecules. We have created the Cancer Therapeutics Response Portal (http://www.broadinstitute.org/ctrp) to enable users to correlate genetic features to sensitivity in individual lineages and control for confounding factors of CCL profiling. We report a candidate dependency, associating activating mutations in the oncogene β-catenin with sensitivity to the Bcl-2 family antagonist, navitoclax. The resource can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs matched to patients by their cancer genotype and lineage.
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Basu
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Bodycombe
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Jaime H
authors.initials: JH
authors.lastname: Cheah
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Price
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Giannina I
authors.initials: GI
authors.lastname: Schaefer
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Ebright
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Stewart
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wang
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Bracha
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Liefeld
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Wawer
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Gilbert
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wilson
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Stransky
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Kryukov
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Vlado
authors.initials: V
authors.lastname: Dancik
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Jordi
authors.initials: J
authors.lastname: Barretina
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: C Suk-Yee
authors.initials: CS
authors.lastname: Hon
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bittker
authors.affiliation: Columbia University, New York, NY 10027, USA.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stockwell
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Dineo
authors.initials: D
authors.lastname: Khabele
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Stern
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: pclemons@broadinstitute.org.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: ashamji@broadinstitute.org.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: stuart_schreiber@harvard.edu.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D045744:Cell Line, Tumor; D062313:Databases, Pharmaceutical; D055808:Drug Discovery; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents