Marinov Marin, Fischer Barbara, Arcaro Alexandre
Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
Crit Rev Oncol Hematol. 2007 Aug;63(2):172-82. doi: 10.1016/j.critrevonc.2007.04.002. Epub 2007 May 30.
Lung cancer is the leading cause of cancer-related mortality in the world, with more than 1 million deaths per year. Over the past years, lung cancer treatment has been based on cytotoxic agents and an improvement in the outcome and quality of life for patients has been observed. However, it has become clear that additional therapeutic strategies are urgently required in order to provide an improved survival benefit for patients. Two major intracellular signaling pathways, the Ras/Raf/extracellular signal-regulated kinase (Erk) and the phosphoinositide 3-kinase (PI3K)/Akt pathways have been extensively studied in neoplasia, including lung cancer. Furthermore, the study of constitutively activated receptor tyrosine kinases (RTKs) and their downstream signaling mediators has opened a promising new field of investigation for lung cancer treatment. Since both the Ras/Raf/Erk and the PI3K/Akt pathways are downstream of a plethora of activated RTKs, they have been extensively studied for the development of novel anti-tumor agents. Moreover, the mammalian target of rapamycin (mTOR) has been identified as a downstream target of the PI3K/Akt pathway. Rapamycin and its derivatives are highly selective and very potent inhibitors of mTOR and initial pre-clinical and clinical studies have reported encouraging results for different tumor types. Nevertheless for lung cancer, this approach has not been successful yet. Here we will review the molecular basis of PI3K/Akt/mTOR signaling in lung cancer and further discuss the therapeutic potential of multi-targeted strategies involving mTOR inhibitors.
肺癌是全球癌症相关死亡的主要原因，每年有超过100万人死亡。在过去的几年里，肺癌治疗一直基于细胞毒性药物，并且观察到患者的治疗效果和生活质量有所改善。然而，很明显，迫切需要额外的治疗策略，以便为患者提供更高的生存获益。两条主要的细胞内信号通路，即Ras/Raf/细胞外信号调节激酶（Erk）和磷酸肌醇3激酶（PI3K）/Akt通路，已在包括肺癌在内的肿瘤形成过程中得到广泛研究。此外，对组成型激活的受体酪氨酸激酶（RTK）及其下游信号介质的研究为肺癌治疗开辟了一个有前景的新研究领域。由于Ras/Raf/Erk和PI3K/Akt通路均位于大量激活的RTK的下游，因此它们已被广泛研究用于开发新型抗肿瘤药物。此外，哺乳动物雷帕霉素靶蛋白（mTOR）已被确定为PI3K/Akt通路的下游靶点。雷帕霉素及其衍生物是mTOR的高度选择性和强效抑制剂，初步的临床前和临床研究已报道了针对不同肿瘤类型的令人鼓舞的结果。然而，对于肺癌而言，这种方法尚未成功。在此，我们将综述肺癌中PI3K/Akt/mTOR信号传导的分子基础，并进一步讨论涉及mTOR抑制剂的多靶点策略的治疗潜力。
