Suzuki, RikioKikuchi, ShoheiHarada, TakeshiMimura, NaoyaMinami, JiroOhguchi, HirotoYoshida, YasuhiroSagawa, MorihikoGorgun, GulluCirstea, DianaCottini, FrancescaJakubikova, JanaTai, Yu-TzuChauhan, DharminderRichardson, PaulMunshi, NikhilAndo, KiyoshiUtsugi, TeruhiroHideshima, TeruAnderson, Kenneth2016-01-042015Suzuki, R., S. Kikuchi, T. Harada, N. Mimura, J. Minami, H. Ohguchi, Y. Yoshida, et al. 2015. “Combination of a Selective HSP90α/β Inhibitor and a RAS-RAF-MEK-ERK Signaling Pathway Inhibitor Triggers Synergistic Cytotoxicity in Multiple Myeloma Cells.” PLoS ONE 10 (12): e0143847. doi:10.1371/journal.pone.0143847. http://dx.doi.org/10.1371/journal.pone.0143847.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993520Heat 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.en-USJournal Article2016-01-0410.1371/journal.pone.0143847