Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer
Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer
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DOI：
10.1172/jci34739
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发表时间：
2008-09-01
影响因子：
15.9
通讯作者：
Pandolfi, Pier Paolo
中科院分区：
文献类型：
--
作者：
Carracedo, Arkaitz;Ma, Li;Pandolfi, Pier Paolo
大量研究已经建立了哺乳动物雷帕霉素靶蛋白（mTOR）异常激活与肿瘤发生之间的因果关系，表明抑制mTOR可能具有治疗潜力。在这项研究中，我们发现雷帕霉素及其类似物激活了人类癌症中的MAPK通路，这代表了一种新的mTO RC1-MAPK反馈回路。我们发现，接受RAD001（一种雷帕霉素衍生物）治疗的晚期实体瘤患者的肿瘤样本显示，MAPK通路的激活随给药计划而增加。RAD001治疗也导致前列腺癌小鼠模型中的MAPK激活。我们进一步表明，雷帕霉素诱导的MAPK激活发生在正常细胞和癌细胞系中，并且这种反馈回路依赖于S6K-PI3K-Ras途径。值得注意的是，在体外和异种移植小鼠模型中，药物抑制MAPK通路增强了雷帕霉素抑制癌细胞mTORC1的抗肿瘤作用。综上所述，我们的研究结果确定了MAPK激活是mTORC1抑制的结果，并强调了mTORC1和MAPK抑制剂联合治疗方法的潜力，目前在临床中作为单一药物用于治疗人类癌症。
Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTO RC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers.