Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual-Inhibitors as a Therapeutic Strategy against Cutaneous T-Cell Lymphoma
Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual-Inhibitors as a Therapeutic Strategy against Cutaneous T-Cell Lymphoma
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DOI：
10.1016/j.jid.2019.08.454
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发表时间：
2020-05-01
影响因子：
6.5
通讯作者：
Narducci, Maria Grazia
中科院分区：
文献类型：
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作者：
Bresin, Antonella;Cristofoletti, Cristina;Narducci, Maria Grazia
磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）通路在许多肿瘤以及皮肤T细胞淋巴瘤（CTCL）中过度活化，所述皮肤T细胞淋巴瘤包括蕈样肉芽肿和称为Sezary综合征（SS）的侵袭性变体。TORC 1信号在SS细胞中被细胞因子和趋化因子激活，这些因子在SS组织中过表达。此外，属于该级联的基因（如PTEN、LKB 1和P70 S6 K）的重复拷贝数变异有助于该途径的超活化。本研究的目的是研究mTOR抑制剂在CTCL中的治疗潜力。我们比较了三种雷帕霉素类似物（雷帕霉素、替西罗莫司和依维莫司）和双重mTOR/PI 3 K抑制剂PF-04691502（下文称为PF-502）在四种CTCL细胞系中的功效。PF-502是最有效的细胞生长抑制剂。有趣的是，PF-502还在患者来源的CTCL细胞和异种移植小鼠模型中发挥了其抗肿瘤活性，在异种移植小鼠模型中，PF-502诱导了显著的细胞凋亡并增加了治疗小鼠的存活率。此外，我们发现PTEN基因表达和PF-502诱导SS细胞凋亡的能力之间呈负相关。我们的数据强烈支持双重PI 3 K/mTOR抑制剂在CTCL中的治疗潜力。
The phosphoinositide 3-kinase(PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway is hyperactivated in many tumors, as well as in cutaneous T-cell lymphoma (CTCL), which includes the mycosis fungoides and the aggressive variant known as Sezary syndrome (SS). TORC1 signaling is activated in SS cells by cytokines and chemokines, which are overexpressed in SS tissues. Furthermore, the recurrent copy number variation of genes belonging to this cascade, such as PTEN, LKB1, and P70S6K, contributes to the hyperactivation of the pathway. The aim of this study was to investigate the therapeutic potential of mTOR inhibitors in CTCL. We compared the efficacy of three rapalogs (rapamycin, temsirolimus, and everolimus) and the dual-mTOR/PI3K inhibitor PF-04691502 (hereinafter PF-502) in four CTCL cell lines. PF-502 was revealed to be the most effective inhibitor of cell growth. Interestingly, PF-502 also exerted its antitumor activity in patient-derived CTCL cells and in a xenograft mouse model, where it induced significant apoptosis and increased survival of treated mice. Furthermore, we found an inverse correlation between PTEN gene expression and the ability of PF-502 to induce apoptosis in SS cells. Our data strongly support the therapeutic potential of dual PI3K/mTOR inhibitors in CTCL.