Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive Tampa, FL 33612, USA.
Biochem Pharmacol. 2010 Sep 1;80(5):613-23. doi: 10.1016/j.bcp.2010.05.014. Epub 2010 May 24.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Platinum-based doublets remain the current standard therapy for advanced NSCLC. However, overall survival (OS) has reached a plateau, even with the improvement in these regimens. Advances in the knowledge of molecular mechanisms of carcinogenesis have prompted the development of many novel molecular-targeted agents including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Results of the recent phase III IPASS trial showed that the EGFR-TKI gefitinib has a superior progression-free survival (PFS) to the most commonly used platinum-based doublet carboplatin-paclitaxel as the first-line chemotherapy for pulmonary lung adenocarcinoma among nonsmokers in East Asia. This trial also demonstrated that the presence of EGFR mutation is the best predictor of gefitinib treatment compared with the other biomarkers including EGFR gene copy number. Despite the therapeutic benefit of EGFR-TKIs in NSCLC, most patients eventually develop resistance to these drugs. A secondary mutation of EGFR (T790M) and amplification of MET account for 70% of all cases of acquired resistance to EGFR-TKIs. This review summarizes the significance of EGFR mutations and the mechanisms of resistance to EGFR-TKIs in NSCLC, both of which are critical for patient selection to extend survival as well as to overcome resistance in NSCLC patients treated with EGFR-TKIs.
非小细胞肺癌（NSCLC）是全球癌症死亡的主要原因。含铂双药化疗仍然是晚期 NSCLC 的标准治疗方法。然而，即使这些方案有所改进，总生存期（OS）也已达到平台期。对致癌分子机制的认识的进步促使了许多新型分子靶向药物的发展，包括表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）。最近的 III 期 IPASS 试验结果表明，EGFR-TKI 吉非替尼在无吸烟史的东亚肺腺癌患者中，与最常用的铂类双药卡铂-紫杉醇相比，具有更优的无进展生存期（PFS），作为一线化疗药物。该试验还表明，与其他生物标志物（包括 EGFR 基因拷贝数）相比，EGFR 突变是吉非替尼治疗的最佳预测因子。尽管 EGFR-TKIs 在 NSCLC 中有治疗作用，但大多数患者最终会对这些药物产生耐药性。EGFR 的二次突变（T790M）和 MET 扩增占 EGFR-TKI 获得性耐药的所有病例的 70%。这篇综述总结了 NSCLC 中 EGFR 突变的意义和对 EGFR-TKIs 的耐药机制，这对于选择患者以延长生存期以及克服 EGFR-TKIs 治疗的 NSCLC 患者的耐药性至关重要。
