TY - JOUR
T1 - Combination of a selective HSP90α/β inhibitor and a RAS-RAF-MEK-ERK signaling pathway inhibitor triggers synergistic cytotoxicity in multiple myeloma cells
AU - Suzuki, Rikio
AU - Kikuchi, Shohei
AU - Harada, Takeshi
AU - Mimura, Naoya
AU - Minami, Jiro
AU - Ohguchi, Hiroto
AU - Yoshida, Yasuhiro
AU - Sagawa, Morihiko
AU - Gorgun, Gullu
AU - Cirstea, Diana
AU - Cottini, Francesca
AU - Jakubikova, Jana
AU - Tai, Yu Tzu
AU - Chauhan, Dharminder
AU - Richardson, Paul G.
AU - Munshi, Nikhil
AU - Ando, Kiyoshi
AU - Utsugi, Teruhiro
AU - Hideshima, Teru
AU - Anderson, Kenneth C.
N1 - Publisher Copyright:
© 2015 Suzuki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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- orBRAF-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.
AB - 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- orBRAF-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.
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U2 - 10.1371/journal.pone.0143847
DO - 10.1371/journal.pone.0143847
M3 - Article
C2 - 26630652
AN - SCOPUS:84955504450
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 12
M1 - e0143847
ER -