bms-754807 and Carcinoma--Squamous-Cell

In head and neck squamous cell carcinoma (HNSCC), resistance to single-agent targeted therapy may be overcome by co-targeting of compensatory signaling pathways.. A targeted drug screen with 120 combinations was used on 9 HNSCC cell lines.. Multiple novel drug combinations demonstrated synergistic growth inhibition. Combining the insulin-like growth factor-1 receptor (IGF-1R) inhibitor, BMS754807, with either the human epidermal growth factor receptor (HER)-family inhibitor, BMS599626, or the Src-family kinase inhibitor, dasatinib, resulted in substantial synergy and growth inhibition. Depending on the cell line, these combinations induced synergistic or additive apoptosis; when synergistic apoptosis was observed, AKT phosphorylation was inhibited to a greater extent than either drug alone. Conversely, when additive apoptosis occurred, AKT phosphorylation was not reduced by the drug combination.. Combined IGF-1R/HER family and IGF-1R/Src family inhibition may have therapeutic potential in HNSCC. AKT may be a node of convergence between IGF-1R signaling and pathways that compensate for IGF-1R inhibition.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carbamates; Carcinoma, Squamous Cell; Cell Culture Techniques; Cell Line, Tumor; Dasatinib; Drug Resistance, Neoplasm; Drug Synergism; Head and Neck Neoplasms; Humans; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyrazoles; Receptor, IGF Type 1; Signal Transduction; Triazines