RT Journal Article
SR Electronic
T1 Selective and Potent Akt Inhibition Triggers Anti-Myeloma Activities and Enhances Fatal Endoplasmic Reticulum Stress Induced by Proteasome Inhibition
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 4458
OP 4469
DO 10.1158/0008-5472.CAN-13-3652
VO 74
IS 16
A1 Mimura, Naoya
A1 Hideshima, Teru
A1 Shimomura, Toshiyasu
A1 Suzuki, Rikio
A1 Ohguchi, Hiroto
A1 Rizq, Ola
A1 Kikuchi, Shohei
A1 Yoshida, Yasuhiro
A1 Cottini, Francesca
A1 Jakubikova, Jana
A1 Cirstea, Diana
A1 Gorgun, Gullu
A1 Minami, Jiro
A1 Tai, Yu-Tzu
A1 Richardson, Paul G.
A1 Utsugi, Teruhiro
A1 Iwama, Atsushi
A1 Anderson, Kenneth C.
YR 2014
UL http://cancerres.aacrjournals.org/content/74/16/4458.abstract
AB The PI3K/Akt pathway plays a crucial role in the pathogenesis of multiple myeloma (MM) in the bone marrow (BM) milieu. However, efficacy of selective and potent Akt inhibition has not yet been fully elucidated. In this study, we, therefore, examined the biologic impact of selective and potent Akt inhibition by a novel allosteric inhibitor TAS-117. TAS-117 induced significant growth inhibition, associated with downregulation of phosphorylated Akt (p-Akt), selectively in MM cell lines with high baseline p-Akt. Cytotoxicity of TAS-117 was also observed in patient MM cells, but not in normal peripheral blood mononuclear cells. Importantly, TAS-117 induced significant cytotoxicity in MM cells even in the presence of BM stromal cells, associated with inhibition of IL6 secretion. Oral administration of TAS-117 significantly inhibited human MM cell growth in murine xenograft models. TAS-117 triggered apoptosis and autophagy, as well as induction of endoplasmic reticulum (ER) stress response with minimal expression of C/EBP homologous protein (CHOP), a fatal ER stress marker. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity, associated with increased CHOP and PARP cleavage and blockade of bortezomib-induced p-Akt, suggesting that TAS-117 augments bortezomib-induced ER stress and apoptotic signaling. Carfilzomib-induced cytotoxicity was similarly enhanced by TAS-117. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity in vivo, associated with prolonged host survival. Our results show that selective and potent Akt inhibition by TAS-117 triggers anti-MM activities in vitro and in vivo, as well as enhances cytotoxicity of proteasome inhibition, providing the preclinical framework for clinical evaluation of selective Akt inhibitors, alone and in combination with proteasome inhibitors in MM. Cancer Res; 74(16); 4458–69. ©2014 AACR.