Dual PI3K/AKT/mTOR Inhibitor BEZ235 Synergistically Enhances the Activity of JAK2 Inhibitor against Cultured and Primary Human Myeloproliferative Neoplasm Cells
Dual PI3K/AKT/mTOR Inhibitor BEZ235 Synergistically Enhances the Activity of JAK2 Inhibitor against Cultured and Primary Human Myeloproliferative Neoplasm Cells
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DOI：
10.1158/1535-7163.mct-12-0862
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发表时间：
2013-05-01
影响因子：
5.7
通讯作者：
Bhalla, Kapil N.
中科院分区：
文献类型：
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作者：
Fiskus, Warren;Verstovsek, Srdan;Bhalla, Kapil N.
来自骨髓增生性肿瘤（MPN）如骨髓纤维化的造血祖细胞（HPC）通常表达突变体JAK 2-V617 F或与JAK-STAT 5/3、RAS/RAF/MAPK和PI 3 K/AKT/mTOR途径的活性增加相关的其他突变。这赋予MPN HPC增殖和存活优势。用JAK酪氨酸激酶抑制剂（TKI），例如TG 101209、TG 101348（SAR 302503）或INCB 018424（ruxolitinib）治疗，抑制突变体JAK 2介导的信号传导。尽管JAK-TKI治疗可有效减轻全身症状和脾肿大，但不能改善骨髓纤维化或显著提高晚期骨髓纤维化患者的生存率。在这里，我们发现用双重磷酸肌醇-3-激酶（PI 3 K）/AKT和mTOR抑制剂BEZ 235处理减弱了PI 3 K/AKT和mTOR信号传导，以及诱导了培养的表达人JAK 2-V617 F的HEL92.1.7（HEL）、UKE 1细胞和原代CD 34+骨髓纤维化（MF）-MPN细胞的细胞周期生长停滞和凋亡。用BEZ 235处理还诱导了针对JAK-TKI抗性选择的JAK 2-TKI抗性HEL/TGR细胞的显著凋亡。BEZ 235和JAK 2-TKI（TG 101209和SAR 302503）的共处理协同诱导了对培养的和原代CD 34 + MPN细胞的致死活性，而相对保留了正常CD 34 + HPC。这些发现为确定双重PI 3 K/mTOR抑制剂与JAK抑制剂组合对骨髓纤维化HPC的体内活性提供了令人信服的理由。
Hemopoietic progenitor cells (HPC) from myeloproliferative neoplasms (MPN) such as myelofibrosis commonly express mutant JAK2-V617F or other mutations that are associated with increased activities of JAK-STAT5/3, RAS/RAF/MAPK, and PI3K/AKT/mTOR pathways. This confers proliferative and survival advantage on the MPN HPCs. Treatment with JAK tyrosine kinase inhibitor (TKI), for example, TG101209, TG101348 (SAR302503), or INCB018424 (ruxolitinib), inhibits mutant JAK2-mediated signaling. Although effective in reducing constitutional symptoms and splenomegaly, treatment with JAK-TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis. Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 cells, and primary CD34+ myelofibrosis (MF)-MPN cells. Treatment with BEZ235 also induced significant apoptosis of the JAK2-TKI resistant HEL/TGR cells that were selected for resistance against JAK-TKI. Cotreatment with BEZ235 and JAK2-TKI (TG101209 and SAR302503) synergistically induced lethal activity against the cultured and primary CD34+ MPN cells while relatively sparing the normal CD34+ HPCs. These findings create a compelling rationale to determine the in vivo activity of dual PI3K/mTOR inhibitors in combination with JAK inhibitors against myelofibrosis HPCs.