非小细胞肺癌第三代ALK抑制剂洛拉替尼的耐药机制及其相关研究进展

Research Progress of the Drug Resistance Mechanism of the Third-Generation ALK Inhibitor Lorlatinib in NSCLC

间变淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合基因是非小细胞肺癌(non-small cell lung cancer,NSCLC)患者除表皮生长因子受体(epidermal growth factor receptor,EGFR)基因之外最常见的驱动基因。ALK融合基因阳性的NSCLC患者能从ALK酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)靶向治疗中明显获益,但是患者最终会发生TKI耐药。探索ALK靶向治疗的耐药机制一直是研究重点。关于第一代和第二代ALK TKIs的耐药机制已有较多报道,第三代ALK TKI洛拉替尼的耐药机制亟待阐述。本文将主要从依赖ALK基因(即on-target resistance)和非依赖ALK基因(即off-target resistance)两方面阐述第三代ALK TKI洛拉替尼的耐药机制,重点总结了经序贯洛拉替尼治疗发生复合突变后对其他TKIs的敏感性以及旁路活化途径,一线洛拉替尼治疗潜在的耐药机制以及第四代ALK TKIs的研究进展,洛拉替尼治疗中液体活检动态监测的意义。

The fusion gene of anaplastic lymphoma kinase(ALK)is the most common driver gene in non-small cell lung cancer(NSCLC)patients,apart from the epidermal growth factor receptor(EGFR)gene.NSCLC patients with positive ALK fusion genes can significantly benefit from targeted treatment with ALK tyrosine kinase inhibitors(TKIs),but ultimately develop TKI resistance.Exploring the resistance mechanism of ALK targeted therapy has always been a research focus.The resistance mechanisms of the first-and second-generation ALK TKIs have been reported multiple times,while the resistance mechanisms of the third-generation ALK TKIs lorlatinib still need further elaboration.This article will mainly focus on the resistance mechanism of third-generation ALK TKI lorlatinib from two aspects:ALK dependent mechanism(on-target resistance)and ALK independent mechanism(off-target resistance),including summarized the sensitivity of compound mutations to other TKIs after sequential treatment with lorlatinib and bypass activation pathway;the potential resistance mechanism of first-line treatment with lorlatinib;the research progress of the fourth generation ALK TKIs,as well as the significance of dynamic monitoring liquid biopsy in the treatment of lorlatinib.