Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis.
Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis.
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DOI：
10.18632/oncotarget.18073
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发表时间：
2017-11-14
期刊：
影响因子：
--
通讯作者：
Vannucchi AM
中科院分区：
文献类型：
--
作者：
Bartalucci N;Calabresi L;Balliu M;Martinelli S;Rossi MC;Villeval JL;Annunziato F;Guglielmelli P;Vannucchi AM
JAK 1/JAK 2抑制剂ruxolitinib抑制JAK 2 V617 F突变细胞中组成性激活的JAK/STAT通路，导致骨髓增生性肿瘤患者的临床获益。然而，改善疾病效果的证据仍然很少;此外，一些患者对ruxolitinib反应不充分，或有一过性反应，因此需要新的治疗策略。在这里，我们证明了鲁索利替尼在JAK 2 V617 F突变细胞中引起STAT 5的不完全抑制，这是由于STAT 5 b的磷酸化丝氨酸残基的持续存在，相反，这些残基被PI 3 K和mTORC 1抑制剂靶向。我们发现STAT 5 b丝氨酸残基的PI 3 K/mTOR依赖性磷酸化涉及蛋白磷酸酶2A及其阻遏物CIP 2A。在携带JAK 2 V617 F突变的细胞中发现CIP 2A的水平增加，并且我们提供了在II期临床试验中接受mTOR抑制剂RAD 001的骨髓纤维化患者中临床应答与CIP 2A下调程度之间相关性的证据。为了实现STAT 5磷酸化的最大抑制，我们将鲁索替尼与BKM 120（一种PI 3 K抑制剂）和RAD 001（一种mTOR抑制剂）组合，在JAK 2 V617 F突变细胞系、原代患者细胞和JAK 2 V617 F敲入小鼠中获得改善的功效。这些发现有助于理解PI 3 K/mTOR抑制剂在MPN中的有效性，并为开发联合临床试验提供了依据。
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors. We found that PI3K/mTOR-dependent phosphorylation of STAT5b serine residues involves Protein Phosphatase 2A and its repressor CIP2A. The levels of CIP2A were found increased in cells harboring the JAK2V617F mutation, and we provide evidence of a correlation between clinical responses and the extent of CIP2A downregulation in myelofibrosis patients receiving the mTOR inhibitor RAD001 in a phase II clinical trial. To achieve maximal inhibition of STAT5 phosphorylation, we combined ruxolitinib with BKM120, a PI3K inhibitor, and RAD001, an mTOR inhibitor, obtaining improved efficacy in JAK2V617F mutated cell lines, primary patients’ cells, and JAK2V617F knock-in mice. These findings contribute to understanding the effectiveness of PI3K/mTOR inhibitors in MPN and argue for the rationale to develop combination clinical trials.
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影响因子：
3.7
作者：
Cardoso BA;Belo H;Barata JT;Almeida AM
通讯作者：
Almeida AM
影响因子：
20.3
作者：
Guglielmelli, Paola;Barosi, Giovanni;Vannucchi, Alessandro M.
通讯作者：
Vannucchi, Alessandro M.
使用JAK和PAN级I PI3K抑制剂对骨髓增生性肿瘤的联合治疗。
影响因子：
5.3
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
通讯作者：
Lee MA
影响因子：
37.3
作者：
Jung HM;Phillips BL;Chan EK
通讯作者：
Chan EK
影响因子：
20.3
作者：
Akada, Hajime;Yan, Dongqing;Mohi, M. Golam
通讯作者：
Mohi, M. Golam