Mimura Naoya, Hideshima Teru, Shimomura Toshiyasu, Suzuki Rikio, Ohguchi Hiroto, Rizq Ola, Kikuchi Shohei, Yoshida Yasuhiro, Cottini Francesca, Jakubikova Jana, Cirstea Diana, Gorgun Gullu, Minami Jiro, Tai Yu-Tzu, Richardson Paul G, Utsugi Teruhiro, Iwama Atsushi, Anderson Kenneth C
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Cellular and Molecular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Cancer Res. 2014 Aug 15;74(16):4458-69. doi: 10.1158/0008-5472.CAN-13-3652. Epub 2014 Jun 16.
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.
PI3K/Akt信号通路在骨髓（BM）微环境中的多发性骨髓瘤（MM）发病机制中起关键作用。然而，选择性和强效Akt抑制的疗效尚未完全阐明。因此，在本研究中，我们研究了新型变构抑制剂TAS-117对Akt进行选择性和强效抑制的生物学影响。TAS-117在基线p-Akt水平高的MM细胞系中诱导了显著的生长抑制，并伴有磷酸化Akt（p-Akt）的下调。在患者MM细胞中也观察到了TAS-117的细胞毒性，但在正常外周血单个核细胞中未观察到。重要的是，即使在存在BM基质细胞的情况下，TAS-117在MM细胞中也诱导了显著的细胞毒性，这与IL6分泌的抑制有关。在小鼠异种移植模型中，口服TAS-117显著抑制了人MM细胞的生长。TAS-117引发了凋亡和自噬，以及内质网（ER）应激反应的诱导，同时作为致命ER应激标志物的C/EBP同源蛋白（CHOP）的表达最低。重要的是，TAS-117增强了硼替佐米诱导的细胞毒性，这与CHOP和PARP裂解增加以及硼替佐米诱导的p-Akt的阻断有关，表明TAS-117增强了硼替佐米诱导的ER应激和凋亡信号。TAS-117同样增强了卡非佐米诱导的细胞毒性。重要的是，TAS-117在体内增强了硼替佐米诱导的细胞毒性，这与宿主生存期延长有关。我们的结果表明，TAS-117对Akt的选择性和强效抑制在体外和体内触发了抗MM活性，同时增强了蛋白酶体抑制的细胞毒性，为选择性Akt抑制剂单独或与蛋白酶体抑制剂联合用于MM的临床评估提供了临床前框架。
