title: Systematic identification of signaling pathways with potential to confer anticancer drug resistance.
abstract: Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)-mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF(V600E) melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Martz
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Ottina
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Singleton
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Jasper
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Wardell
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Peraza-Penton
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
authors.forename: Gray R
authors.initials: GR
authors.lastname: Anderson
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Winter
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Alley
authors.affiliation: University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
authors.affiliation: University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Tetzlaff
authors.affiliation: University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Rathmell
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu kris.wood@duke.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA. sabatini@wi.mit.edu kris.wood@duke.edu.
authors.forename: Kris C
authors.initials: KC
authors.lastname: Wood
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins