Reference Detail

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 Cancer research
Vol 77
Issue 2
Date 2017 Jan 15
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 Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
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
Unknown unknown triple-receptor negative breast cancer not applicable Bortezomib Preclinical - Cell culture Actionable In a preclinical study, Velcade (bortezomib) induced complete growth inhibition of triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098
Unknown unknown triple-receptor negative breast cancer not applicable KP372-1 Preclinical - Cell culture Actionable In a preclinical study, KP372-1 induced complete growth inhibition of triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098
Unknown unknown triple-receptor negative breast cancer not applicable Cabozantinib + Navitoclax Preclinical - Cell culture Actionable In a preclinical study, the combination of Navitoclax (ABT-263) and Cometriq (cabozantinib) resulted in a synergistic effect and inhibited the growth of triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098
Unknown unknown triple-receptor negative breast cancer not applicable Navitoclax + Paclitaxel Preclinical - Cell culture Actionable In a preclinical study, the combination of Navitoclax (ABT-263) and Taxol (paclitaxel) resulted in a synergistic effect and inhibited the growth of triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098
Unknown unknown triple-receptor negative breast cancer not applicable Carfilzomib Preclinical - Cell culture Actionable In a preclinical study, Kyprolis (carfilzomib) induced complete growth inhibition of triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098
Unknown unknown triple-receptor negative breast cancer not applicable Everolimus + MK-1775 Preclinical - Cell culture Actionable In a preclinical study, the combination of Afinitor (everolimus) and MK-1775 resulted in a synergistic effect in triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098
Unknown unknown triple-receptor negative breast cancer not applicable JQ1 + Paclitaxel Preclinical - Cell culture Actionable In a preclinical study, the combination of JQ1 and Taxol (paclitaxel) resulted in a synergistic effect and inhibited the growth of triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098
Unknown unknown triple-receptor negative breast cancer not applicable BAY 11-7082 + Erlotinib Preclinical - Cell culture Actionable In a preclinical study, the combination of BAY 11-7082 and Tarceva (erlotinib) resulted in a synergistic effect in triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098
Unknown unknown triple-receptor negative breast cancer not applicable Crizotinib + Navitoclax Preclinical - Cell culture Actionable In a preclinical study, the combination of Navitoclax (ABT-263) and Xalkori (crizotinib) resulted in a synergistic effect and inhibited the growth of triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098
Unknown unknown triple-receptor negative breast cancer not applicable Nutlin-3 + Paclitaxel Preclinical - Cell culture Actionable In a preclinical study, the combination of Nutlin-3 and Taxol (paclitaxel) resulted in a synergistic effect and inhibited the growth of triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098
Unknown unknown triple-receptor negative breast cancer not applicable YM155 Preclinical - Cell culture Actionable In a preclinical study, YM155 induced complete growth inhibition of triple-receptor negative breast cancer cells in culture (PMID: 27872098). 27872098