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Ref Type Journal Article
PMID (27872098)
Authors Wali VB, Langdon CG, Held MA, Platt JT, Patwardhan GA, Safonov A, Aktas B, Pusztai L, Stern DF, Hatzis C
Title Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 77 2 2017 Jan 15 566-578 Cancer Res
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References