Department of Thoracic/Head and Neck Medical Oncology, UT/MD Anderson Cancer Center, Houston, Texas 77030 , USA.
J Thorac Oncol. 2012 Aug;7(8):1315-26. doi: 10.1097/JTO.0b013e31825493eb.
Lung cancer is a common disease with more than 1.6 million new cases diagnosed worldwide in 2008. Treatments for patients with advanced disease are rarely curative, and responses to therapy are often followed by relapse, which highlights the large unmet need for novel therapies. Recent advances in cancer treatment have focused on personalized therapy, whereby patients are treated with agents that best target the molecular drivers of their disease. Thus, a better understanding of the pathways that drive cancer or drug resistance is of critical importance. One such example is the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, which is activated in many lung cancer patients and represents a target for therapy. PI3K/AKT/mTOR pathway activation has also been observed in tumors resistant to agents targeting upstream receptor tyrosine kinases. Agents that target this pathway have the potential to shut down survival pathways, and are being explored both in the setting of pathway-activating mutations and for their ability to restore sensitivity to upstream signaling targeted agents. Here, we examine the frequency of mutations activating the PI3K/AKT/mTOR pathway, review the novel agents being explored to target this pathway, and explore the potential role of the inhibition of this pathway in the clinical development of these agents.
肺癌是一种常见疾病，2008 年全球新诊断病例超过 160 万例。晚期疾病患者的治疗方法很少具有治愈性，并且治疗后的反应常常是复发，这突显了对新型治疗方法的巨大需求未得到满足。癌症治疗的最新进展集中在个性化治疗上，即根据患者疾病的分子驱动因素，用最能靶向这些因素的药物对患者进行治疗。因此，更好地了解驱动癌症或耐药性的途径至关重要。例如，磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）途径在许多肺癌患者中被激活，是治疗的一个靶点。PI3K/AKT/mTOR 途径的激活也在对靶向上游受体酪氨酸激酶的药物耐药的肿瘤中观察到。针对该途径的药物有可能关闭生存途径，目前正在对其进行研究，以评估其在具有该途径激活突变的情况下以及恢复对上游信号靶向药物的敏感性方面的潜力。在这里，我们检查了激活 PI3K/AKT/mTOR 途径的突变的频率，回顾了正在探索用于靶向该途径的新型药物，并探讨了抑制该途径在这些药物临床开发中的潜在作用。
