The dual PI3K/mTOR inhibitor PI-103 promotes immunosuppression, in vivo tumor growth and increases survival of sorafenib-treated melanoma cells
The dual PI3K/mTOR inhibitor PI-103 promotes immunosuppression, in vivo tumor growth and increases survival of sorafenib-treated melanoma cells
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DOI：
10.1002/ijc.24926
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发表时间：
2010-04-01
影响因子：
6.4
通讯作者：
Recio, Juan A.
中科院分区：
文献类型：
--
作者：
Lopez-Fauqued, Marta;Gil, Rosa;Recio, Juan A.
黑色素瘤是人类最致命的皮肤癌。如果发生转移，它会变得非常具有侵袭性，并对标准的抗癌治疗方式产生抵抗力。在过去的10年里，已经测试了几种治疗策略，包括使用单一和联合使用小剂量药物。实验结果表明，RAS和PI3K通路在黑色素瘤的发生和维持中起重要作用。在这项研究中，我们评估了PI3K(p110α)/mTOR抑制剂PI-103和BRAF抑制剂索拉非尼单独或联合使用对原代黑色素瘤细胞株的体外和体内抑制作用。PI-103和索拉非尼对体外培养的黑色素瘤细胞的增殖和活力均有抑制作用，但对RAS通路的抑制作用更强。两种药物联合应用在体外对RAS和PI3K信号通路有协同抑制作用，且呈细胞依赖关系。然而，在阻断免疫活性小鼠体内肿瘤生长方面没有观察到协同作用。与预期相反，数据表明PI-103诱导了免疫抑制，促进了体内肿瘤的生长，抑制了细胞凋亡。此外，对PI3K/mTOR抑制剂在肿瘤细胞系中的作用的体外研究表明，PI-103诱导了抗凋亡的BH3家族蛋白MCL1、BCL2和Bcl(XL)，有利于索拉非尼处理的黑色素瘤细胞的体外存活。这些数据无疑为在进行临床研究之前调查合理药物组合对免疫活性动物模型的意外影响提供了论据。
Melanoma is the most lethal human skin cancer. If metastatic, it becomes very aggressive and resistant to standard modalities of anticancer treatment. During the last 10 years, several therapeutic strategies have been tested including the use of single and combined small drugs. Experimental results indicate that RAS and PI3K pathways are important for the development and maintenance of melanoma. In this study, we assessed the in vitro and in vivo inhibition potential of PI-103, a PI3K (p110 alpha)/mTOR inhibitor and sorafenib, a BRAF inhibitor, as single agents and in combination in primary melanoma cell lines. Although PI-103 and sorafenib inhibited melanoma in vitro cell proliferation and viability, the inhibition of RAS pathway appeared to be more effective. The combination of the two agents in in vitro showed a synergistic effect inhibiting RAS and PI3K pathways in a cell line dependent manner. However, no cooperative effect was observed in blocking in vivo tumor growth in immunocompetent mice. In contrary to the expected, the data indicate that PI-103 induced immunosuppression promoting in vivo tumor growth and inhibiting apoptosis. Furthermore, in vitro studies examining the effects of the PI3K/mTOR inhibitor in tumor derived cell lines indicated that PI-103 induced the anti-apoptotic BH3 family proteins Mcl1, Bcl2 and Bcl(XL) favoring, the in vitro survival of sorafenib treated melanoma cells. These data certainly makes an argument for investigating unexpected effects of rational drug combinations on immunocompetent animal models prior to conducting clinical studies.