ALK阳性非小细胞肺癌靶向治疗及其耐药机制的研究进展

Progress of Targeted Therapy and Drug Resistance Mechanism of ALK Positive Non-small Cell Lung Cancer

非小细胞肺癌(Non-small cell lung cancer,NSCLC)是肺癌中最常见的组织学类型。目前,随着分子生物学的发展,我们发现肺癌的发生发展与肿瘤驱动基因密切相关,其中已明确的有表皮生长因子受体(Epidermal growth factor receptor,EGFR)和间变性淋巴瘤激酶(Anaplastic lymphoma kinase,ALK)。现已有针对它们的药物面世,如克唑替尼就是针对ALK阳性NSCLC的酪氨酸激酶抑制剂,临床上的运用明显改善了这类患者的生存。但是在进行ALK TKI的靶向治疗中不可避免地遇到耐药问题,耐药机制包括有:ALK继发性耐药突变、其他致癌驱动程序的活化,如EGFR突变或磷酸化、KRAS突变等。针对出现的耐药也出现了相应的治疗策略,例如二代ALK抑制剂的出现等。我们将对ALK融合基因阳性的NSCLC患者的治疗、耐药机制及耐药后的治疗策略进行综述。

Non-small cell lung cancer is the most common histological type of lung cancer. At present, with the development of molecular biology,we found that the occurrence and development of lung cancer driving genes, which has made it clear to the epidermal growth factor receptor andanaplastic lymphoma kinase. There have been some drugs available for them, such as the tyrosine kinase inhibitor ALK positive NSCLC tyrosinekinase inhibitors, clinical use significantly improved the survival of these patients. However, it is inevitable to encounter drug resistance in targetedtherapy for TKI ALK, the mechanisms include: ALK secondary resistance mutation and other oncogenic driver activation, such as EGFR mutationor phosphorylation, KRAS mutation. In view of the emergence of drug resistance also appeared the corresponding treatment strategies, such asthe emergence of the two generation of ALK inhibitors, etc. In this manuscript, we summarized ALK fusion gene positive NSCLC patients, drugresistance mechanism and the treatment strategy after drug resistance.