title: Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer.
abstract: Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity, and were validated in low-throughput experiments. Principal component analysis revealed that a fraction of all upregulated or downregulated genes of a particular targeted pathway could partly explain cell sensitivity toward agents targeting that pathway. Combination therapies deemed immediately tractable to translation included ABT-263/crizotinib, ABT-263/paclitaxel, paclitaxel/JQ1, ABT-263/XL-184, and paclitaxel/nutlin-3, all of which exhibited synergistic antiproliferative and apoptotic activity in multiple TNBC backgrounds. Mechanistic investigations of the ABT-263/crizotinib combination offering a potentially rapid path to clinic demonstrated RTK blockade, inhibition of mitogenic signaling, and proapoptotic signal induction in basal and mesenchymal stem-like TNBC. Our findings provide preclinical proof of concept for several combination treatments of TNBC, which offer near-term prospects for clinical translation. Cancer Res; 77(2); 566-78. ©2016 AACR.
authors.affiliation: Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut. vikram.wali@yale.edu christos.hatzis@yale.edu.|Yale Cancer Center, New Haven, Connecticut.
authors.forename: Vikram B
authors.initials: VB
authors.lastname: Wali
authors.affiliation: Department of Pathology, Yale School of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Casey G
authors.initials: CG
authors.lastname: Langdon
authors.affiliation: Department of Pathology, Yale School of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Held
authors.affiliation: Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut.
authors.forename: James T
authors.initials: JT
authors.lastname: Platt
authors.affiliation: Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Gauri A
authors.initials: GA
authors.lastname: Patwardhan
authors.affiliation: Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Anton
authors.initials: A
authors.lastname: Safonov
authors.affiliation: Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Bilge
authors.initials: B
authors.lastname: Aktas
authors.affiliation: Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut.|Yale Cancer Center, New Haven, Connecticut.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: Yale Cancer Center, New Haven, Connecticut.|Department of Pathology, Yale School of Medicine, Yale University, New Haven, Connecticut.
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
authors.affiliation: Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut. vikram.wali@yale.edu christos.hatzis@yale.edu.|Yale Cancer Center, New Haven, Connecticut.
authors.forename: Christos
authors.initials: C
authors.lastname: Hatzis
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D025341:Principal Component Analysis; D064726:Triple Negative Breast Neoplasms