Highly selective HSP90 inhibitor, pimitespib, demonstrates its potent growth suppressive activity to adult T-cell leukemia in preclinical models (Pt1-3).. Highly selective HSP90 inhibitor, pimitespib, demonstrates its potent growth suppressive activity to adult T-cell leukemia in preclinical models (Pt1-3).

Adult T-cell leukaemia-lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1). ATL cells constitutively activate anti-apoptotic signals through nuclear factor kappaB (NF-κB)-mediated gene expression. The molecular chaperon heat shock protein 90 (HSP90) plays a crucial role on NF-κB-mediated anti-apoptotic activity in ATL cells and HSP90 inhibitors, such as 17-DMAG and NVP-AUY922, have demonstrated their anti-ATL activities. A novel class of orally active inhibitors of cytosolic HSP90α and β, pimitespib, demonstrated its highly selective anti-ATL cell effects both ex-vivo and in vivo preclinical models. Ten ATL-related cell lines achieved their IC50 below 0.5µM dose of TAS-116 while CD4 lymphocytes derived from healthy donors were less harmed than ATL cells. TAS-116 efficiently induces Tax-degradation and IκB-α accumulation to Tax-positive cell-lines. DNA microarray profiling followed by a variety of pathway analysis revealed that TAS-116 down-regulated NF-κB activating pathways in Tax-positive cells and cell cycle promoting pathways in Tax-negative cells and induces anti-ATL effect. Oral administration of TAS-116 to ATL-cell xenograft model mice also demonstrated the growth inhibitory effects against tumor cells. Consequently, TAS-116, one of the most evolved HSP90 inhibitor, may become a promising option against ATL therapy. Overall design: To identify differentially expressed genes after the treatment with TAS-116, ATL cells from patients were treated with DMSO or TAS-116 for 16h. Then, total RNAs were collected from these cells and subsequently subjected to gene expression microarray analysis.

成人T细胞白血病/淋巴瘤（Adult T-cell leukaemia-lymphoma, ATL）是由人类T细胞嗜淋巴病毒I型（human T-lymphotropic virus type I, HTLV-1）引发的、对化疗高度耐受的外周T淋巴细胞恶性肿瘤。ATL细胞通过核因子κB（nuclear factor kappaB, NF-κB）介导的基因表达，持续性激活抗凋亡信号通路。分子伴侣热休克蛋白90（heat shock protein 90, HSP90）在ATL细胞中NF-κB介导的抗凋亡活性中发挥关键作用；而HSP90抑制剂（如17-DMAG、NVP-AUY922）已被证实具有抗ATL活性。新型胞质型HSP90α和β口服抑制剂匹美司特（pimitespib）在体外及体内临床前模型中均展现出高度选择性的抗ATL细胞效应。10株ATL相关细胞系在TAS-116浓度低于0.5μM时即可达到半数抑制浓度（IC50），而健康供体来源的CD4阳性T淋巴细胞所受损伤显著轻于ATL细胞。TAS-116可有效诱导Tax蛋白降解并促进Tax阳性细胞株中IκB-α的积累。通过DNA微阵列分析结合多组通路富集分析，结果显示TAS-116可下调Tax阳性细胞中的NF-κB激活通路，以及Tax阴性细胞中的细胞周期促进通路，进而发挥抗ATL效应。将TAS-116经口给药至ATL细胞异种移植模型小鼠体内后，同样观察到其对肿瘤细胞的生长抑制作用。综上，作为目前最前沿的HSP90抑制剂之一，TAS-116有望成为ATL治疗的潜在优选方案。
实验设计概述：为鉴定TAS-116处理后差异表达的基因，将患者来源的ATL细胞用二甲基亚砜（dimethyl sulfoxide, DMSO）或TAS-116处理16小时。随后收集这些细胞的总RNA，进行基因表达微阵列分析。