Combination of a selective HSP90α/β inhibitor and a RAS-RAF-MEK-ERK signaling pathway inhibitor triggers synergistic cytotoxicity in multiple myeloma cells

Rikio Suzuki, Shohei Kikuchi, Takeshi Harada, Naoya Mimura, Jiro Minami, Hiroto Ohguchi, Yasuhiro Yoshida, Morihiko Sagawa, Gullu Gorgun, Diana Cirstea, Francesca Cottini, Jana Jakubikova, Yu Tzu Tai, Dharminder Chauhan, Paul G. Richardson, Nikhil Munshi, Kiyoshi Ando, Teruhiro Utsugi, Teru Hideshima, Kenneth C. Anderson

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere0143847
JournalPloS one
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Suzuki, R., Kikuchi, S., Harada, T., Mimura, N., Minami, J., Ohguchi, H., Yoshida, Y., Sagawa, M., Gorgun, G., Cirstea, D., Cottini, F., Jakubikova, J., Tai, Y. T., Chauhan, D., Richardson, P. G., Munshi, N., Ando, K., Utsugi, T., Hideshima, T., & Anderson, K. C. (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]. https://doi.org/10.1371/journal.pone.0143847