tas-116 and Multiple-Myeloma

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Boronic Acids; Bortezomib; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins; Humans; Mice; Mice, SCID; Monomeric GTP-Binding Proteins; Multiple Myeloma; Mutation; Neoplasm Transplantation; Pyrazines; Pyrazoles; Retinal Pigment Epithelium

Heat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90α/β inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM.

Topics: Apoptosis; Benzamides; Benzimidazoles; Bortezomib; Cell Line, Tumor; Doxorubicin; Drug Screening Assays, Antitumor; Genes, ras; HSP90 Heat-Shock Proteins; Humans; Imidazoles; MAP Kinase Signaling System; Multiple Myeloma; Oximes; Proto-Oncogene Proteins B-raf; Pyrazoles