Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors.
Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors.
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使用JAK和PAN级I PI3K抑制剂对骨髓增生性肿瘤的联合治疗。
DOI：
10.1111/jcmm.12156
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发表时间：
2013-11
影响因子：
5.3
通讯作者：
Lee MA
中科院分区：
文献类型：
--
作者：
Choong ML;Pecquet C;Pendharkar V;Diaconu CC;Yong JW;Tai SJ;Wang SF;Defour JP;Sangthongpitag K;Villeval JL;Vainchenker W;Constantinescu SN;Lee MA
目前用于骨髓增生性肿瘤（MPN）治疗的JAK2抑制剂的特异性不足以选择性地抑制异常的JAK2信号传导并保持生理的JAK2信号传导。我们测试了JAK2抑制剂与一系列丝氨酸苏氨酸激酶抑制剂（针对9种信号通路并已用于临床试验）联合是否协同抑制表达突变型和野生型JAK2 （V617F）或血小板生成素受体（W515L）的造血细胞的生长。在15种激酶抑制剂中，经Chou和Talalay分析，ZSTK474磷脂酰肌醇-3 ' -激酶（PI3K）抑制剂分子与JAK2和JAK2/JAK1抑制剂表现出较强的协同抑制作用。其他泛I类，但不是γ或δ特异性PI3K抑制剂，也与JAK2抑制剂协同作用。在Bcr-Abl转化的细胞中未观察到协同作用。用表达TpoR和JAK2 V617F的Ba/F3细胞接种裸鼠后，最佳的JAK2/JAK1和PI3K抑制剂组合对（ruxolitinib和GDC0941）可减轻脾脏重量。它还对来自MPN患者和JAK2 V617F敲入小鼠的不依赖红细胞生成素的红系菌落有很强的抑制作用，在一定剂量下，检测到对JAK2 V617F突变祖细胞的优先抑制。我们的数据支持JAK2和pan- I类PI3K抑制剂联合用于治疗mpn。
Current JAK2 inhibitors used for myeloproliferative neoplasms (MPN) treatment are not specific enough to selectively suppress aberrant JAK2 signalling and preserve physiological JAK2 signalling. We tested whether combining a JAK2 inhibitor with a series of serine threonine kinase inhibitors, targeting nine signalling pathways and already used in clinical trials, synergized in inhibiting growth of haematopoietic cells expressing mutant and wild-type forms of JAK2 (V617F) or thrombopoietin receptor (W515L). Out of 15 kinase inhibitors, the ZSTK474 phosphatydylinositol-3′-kinase (PI3K) inhibitor molecule showed strong synergic inhibition by Chou and Talalay analysis with JAK2 and JAK2/JAK1 inhibitors. Other pan-class I, but not gamma or delta specific PI3K inhibitors, also synergized with JAK2 inhibitors. Synergy was not observed in Bcr-Abl transformed cells. The best JAK2/JAK1 and PI3K inhibitor combination pair (ruxolitinib and GDC0941) reduces spleen weight in nude mice inoculated with Ba/F3 cells expressing TpoR and JAK2 V617F. It also exerted strong inhibitory effects on erythropoietin-independent erythroid colonies from MPN patients and JAK2 V617F knock-in mice, where at certain doses, a preferential inhibition of JAK2 V617F mutated progenitors was detected. Our data support the use of a combination of JAK2 and pan-class I PI3K inhibitors in the treatment of MPNs.
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影响因子：
5.6
作者：
Abe, Miyuki;Funakoshi-Tago, Megumi;Kasahara, Tadashi
通讯作者：
Kasahara, Tadashi
影响因子：
20.3
作者：
Guglielmelli, Paola;Barosi, Giovanni;Vannucchi, Alessandro M.
通讯作者：
Vannucchi, Alessandro M.
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通讯作者：
Saad, MJA
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5.7
作者：
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通讯作者：
Bhalla, Kapil N.
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作者：
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通讯作者：
Slingerland, Joyce M.