《生命科学》 2011, 23(4): 353-358

非小细胞肺癌靶向治疗的临床前研究进展

谭晓红，杨　晓^*

(军事医学科学院生物工程研究所，发育和疾病遗传学研究室，蛋白质组学国家重点实验室，北京 100071)

摘　要：摘　要：针对表皮生长因子受体(EGFR)和血管生成(angiogenesis)信号通路的靶向治疗已经在晚期非小细胞肺癌的治疗上取得成功，但由于抗药性的存在，大多数晚期患者的生存时间仍然提高有限。继发性的EGFR T790M突变和原癌基因肝细胞生长因子受体(MET)的扩增被鉴定为两种主要的抗药机制。最近转化生长因子-β(TGF-β)/白介素-6信号通路被报道能介导选择性和适应性地对erlotinib的抗药。另一方面，Kras突变所致肺癌的靶向治疗方面也取得了一些进展。双重抑制磷脂酰肌醇3-激酶(PI3K)和促分裂素原活化蛋白激酶激酶(MEK)信号通路可导致Kras突变肿瘤的显著消退，联合抑制SRC、PI3K和MEK可使丝氨酸/苏氨酸蛋白激酶11(Lkb1)缺失，Kras突变的肺癌小鼠的肿瘤明显消退，抑制核因子-κB(NF-κB)信号通路导致p53缺失，Kras突变的肿瘤发展显著减慢。这些发现都为发展非小细胞肺癌患者的靶向治疗提供了有力的支持。
关键词：非小细胞肺癌；EGFR；Kras；靶向治疗

Preclinical progress in targeted therapies for non-small cell lung cancer

TAN Xiao-Hong， YANG Xiao^*

(State Key Laboratory of Proteomics， Genetic Laboratory of Development and Diseases， Institute of Biotechnology， Academy of Military Medical Sciences， Beijing 100071， China)

Abstract: Abstract: Targeted therapies against the epidermal growth factor receptor (EGFR) and angiogenesis pathways for advanced non-small cell lung cancer (NSCLC) have been successful， but the survival for most patients remains modest due to resistance to EGFR inhibitors. Secondary EGFR T790M mutation and amplification of MET oncogene were identified as two principal mechanisms of drug resistance. TGF-β/IL-6 axis was reported to mediate selective and adaptive mechanisms of resistance to erlotinib recently. On the other hand， some progress was achieved in targeted treatments for Kras mutated lung cancer. Dual inhibition of PI3K and MEK signaling pathways resulted in marked Kras-mutated tumor regression. Combined inhibition of SRC， PI3K and MEK led to significant tumor regression in Lkb1-deficient， Kras mutated murine lung cancer model.  Inhibition of NF-κB pathway resulted in significantly reduced， p53-deficient， Kras mutated tumor development in vivo. All these findings provide potent support for the development of targeted therapies for NSCLC patients.
Key words: non-small cell lung cancer; EGFR; Kras; targeted therapies