Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.
J Thorac Oncol. 2011 May;6(5):852-63. doi: 10.1097/JTO.0b013e31820e1a25.
Human malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by frequent resistance to chemotherapy and radiotherapy. Here, we investigated the feasibility of mammalian target of rapamycin (mTOR) inhibition by temsirolimus as an antimesothelioma strategy.
Phosphorylation of mTOR (p-mTOR) was assessed by immunohistochemistry in MPM surgical specimens (n = 70). Activation of mTOR and impact of mTOR inhibition by temsirolimus was determined in MPM cell lines in vitro (n = 6) and in vivo as xenografts in severe combined immunodeficiency mice (n = 2) either as single agent or in combination with cisplatin.
Strong immunoreactivity for p-mTOR was predominantly detected in epitheloid and biphasic but not sarcomatoid MPM specimens while adjacent normal tissues remained widely unstained. Accordingly, all mesothelioma cell lines harbored activated mTOR, which was further confirmed by hyperphosphorylation of the downstream targets pS6K, S6, and 4EBP1. Temsirolimus potently blocked mTOR-mediated signals and exerted a cytostatic effect on mesothelioma cell lines in vitro cultured both as adherent monolayers and as nonadherent spheroids. Mesothelioma cells with intrinsic or acquired cisplatin resistance exhibited hypersensitivity against temsirolimus. Accordingly, cisplatin and temsirolimus exerted synergistic inhibition of the mTOR downstream signals and enhanced growth inhibition and/or apoptosis induction in mesothelioma cell lines. Finally, temsirolimus was highly active against MPM xenograft models in severe combined immunodeficiency mice both as a single agent and in combination with cisplatin.
The mTOR inhibitor temsirolimus is active against mesothelioma in vitro and in vivo and synergizes with chemotherapy. These data suggest mTOR inhibition as a promising novel therapeutic strategy against MPM.
人类恶性胸膜间皮瘤（MPM）是一种与石棉有关的恶性肿瘤，其特征是经常对化疗和放疗产生耐药性。在这里，我们研究了雷帕霉素（temsirolimus）抑制哺乳动物雷帕霉素靶蛋白（mTOR）作为抗间皮瘤策略的可行性。
通过免疫组化检测 MPM 手术标本中的 mTOR 磷酸化（p-mTOR）（n=70）。在体外（n=6）和体内作为严重联合免疫缺陷小鼠的异种移植物（n=2）中，研究 mTOR 的激活及其对 mTOR 抑制剂 temsirolimus 的反应，无论是作为单一药物还是与顺铂联合使用。
p-mTOR 的强免疫反应性主要在上皮样和双相型但不是肉瘤样 MPM 标本中检测到，而相邻的正常组织仍然广泛未染色。因此，所有间皮瘤细胞系均存在激活的 mTOR，这进一步通过下游靶标 pS6K、S6 和 4EBP1 的过度磷酸化得到证实。雷帕霉素可有效地阻断 mTOR 介导的信号，并对体外培养的贴壁单层和非贴壁球体形式的间皮瘤细胞系产生细胞生长抑制作用。具有内在或获得性顺铂耐药性的间皮瘤细胞对雷帕霉素表现出超敏性。因此，顺铂和雷帕霉素对间皮瘤细胞系的 mTOR 下游信号产生协同抑制作用，并增强生长抑制和/或凋亡诱导。最后，雷帕霉素在严重联合免疫缺陷小鼠的 MPM 异种移植模型中作为单一药物和与顺铂联合使用均具有高度活性。
mTOR 抑制剂雷帕霉素对体内外间皮瘤均有活性，并与化疗协同作用。这些数据表明，mTOR 抑制作为一种有前途的治疗恶性胸膜间皮瘤的新策略。
