Rationale for targeting the PI3K/Akt/mTOR pathway in myeloproliferative neoplasms.
Rationale for targeting the PI3K/Akt/mTOR pathway in myeloproliferative neoplasms.
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DOI：
10.1016/j.clml.2013.07.011
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发表时间：
2013-09-01
期刊：
影响因子：
--
通讯作者：
Vannucchi, Alessandro M
中科院分区：
文献类型：
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作者：
Bartalucci, Niccolo;Guglielmelli, Paola;Vannucchi, Alessandro M
慢性骨髓增生性肿瘤（MPN）的特征是Janus激酶（JAK）-2 V617 F点突变，但这种分子异常本身并不能解释这些疾病的发病机制，或与原发性血小板增多症、真性红细胞增多症（PV）和骨髓纤维化相关的表型多样性。除了JAK/信号转导子和转录激活子网络之外，还描述了MPN中的大量分子改变，包括磷法替地肌醇-3-chinasi（PI 3 K）/蛋白激酶B（Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）途径组成性激活。开发了几种途径抑制剂，包括依维莫司，直到最新一类的催化抑制剂，如BKM 120和BEZ 235。在这篇综述中，我们提出了一些临床和实验证据表明，PI 3 K/Akt/mTOR通路可能是MPN的治疗靶点。在体外研究中，已显示依维莫司抑制人和鼠JAK 2 V617 F突变细胞系中的细胞增殖和克隆形成潜力。与健康对照组相比，PV和原发性骨髓纤维化患者的造血祖细胞对依维莫司的敏感性显著增加。令人感兴趣的是，依维莫司和JAK 1/2抑制剂ruxolitinib的组合在诱导细胞周期停滞和阻断细胞增殖方面显示出强烈的协同作用。使用双重PI 3 K/mTOR抑制剂BEZ 235获得了类似的数据，其活性也在临床前鼠模型中显示。依维莫司治疗骨髓纤维化的一项多中心I/II期试验记录了在脾脏缩小和全身症状和瘙痒消退方面耐受良好的临床疗效。这些观察结果表明，PI 3 K/Akt/mTOR通路可能是MPN治疗的新靶点。JAK 2抑制剂在体外表现出的协同作用可以基于不同途径的同时靶向打开额外的治疗可能性，这可能优化疗效并降低患者的毒性。
The chronic myeloproliferative neoplasms (MPNs), are characterized by a Janus Kinase (JAK)-2 V617F point mutation but this molecular abnormality does not explain by itself the pathogenesis of these disorders, or the phenotypic diversity associated with essential thrombocythemia, polycythemia vera (PV), and myelofibrosis. Beyond the JAK/signal transducer and activator of transcription network, a wide number of molecular alterations were described in MPN including the fosfatidilinositolo-3-chinasi (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway constitutive activation. Several pathway inhibitors were developed, including everolimus, up to the latest class of catalytic inhibitors such as BKM120 and BEZ235. In this review, we present some clinical and experimental evidence showing that the PI3K/Akt/mTOR pathway could represent a therapeutic target in MPNs. In in vitro studies, everolimus has been shown to inhibit cell proliferation and clonogenic potential in human and murine JAK2 V617F mutated cell lines. Patients with PV and primary myelofibrosis hematopoietic progenitors were significantly more sensitive to everolimus compared with healthy control subjects. Of much interest, a combination of everolimus and the JAK1/2 inhibitor, ruxolitinib, showed strong synergism in inducing cell cycle arrest and blockade of cell proliferation. Similar data were obtained using a dual PI3K/mTOR inhibitor, BEZ235, with activity that was also shown in preclinical murine models. A multicenter phase I/II trial with everolimus in myelofibrosis documented a well tolerated clinical efficiency in terms of spleen size reduction and resolution of systemic symptoms and pruritus. These observations indicate that the PI3K/Akt/mTOR pathway might represent a novel target for treatment in MPN. The synergism demonstrated in vitro with JAK2 inhibitors could open additional therapeutic possibilities based on concurrent targeting of different pathways that might optimize efficacy and reduce toxicity in patients.