ALK阳性非小细胞肺癌患者克唑替尼耐药的机制和治疗措施

Treatment of Patients with ALK Gene Rearranged Non-small Cell Lung Cancer after Resistance to Crizotinib

肺癌是全球发病率和致死率最高的疾病之一。非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌最为常见的组织学类型。近些年,分子生物学的发展让我们对NSCLC的认识从组织水平深入到分子水平。表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变和间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合基因是NSCLC患者最为重要的两个肿瘤驱动基因。针对它们的酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)显著改善了带有这类分子特征的NSCLC患者的生存。不幸的是,目前几乎所有针对这两种突变的初始靶向治疗都会不可避免地出现耐药问题。有关EGFR-TKIs的耐药机制及其应对策略已经有很多文章进行阐述,而对于ALK TKIs治疗后出现耐药问题的机制和相应的治疗策略还未曾有过详细的综述。因此,本文针对一代ALK TKI(克唑替尼)治疗ALK融合基因阳性的NSCLC患者(ALK+NSCLC)后引起耐药问题的机制和有关后续治疗策略做一综述。

Lung cancer is the common lethal disease with the highest morbidity and mortality worldwide. Non-small cell lung cancer （NSCLC） is the most common histological type of lung cancer. Recently, the advances in the molecular biology have transformed our view of NSCLC from histopathological descriptions to precise molecular and genetic identities that can be resolved to single-cell level. Epidermal growth factor receptor （EGFR） and anaplastic lymphoma kinase （ALK） are the most crucial tumor driver genes in NSCLC. hTeir tyrosine kinase inhibitors （TKIs） can signiifcantly improve survival of these patients, who have these driver genes’ mutation. Unfortunately, drug resistance would inevitably occur atfer almost all of initial targeted therapy. hTe resistance mechanism and corresponding methods on EGFR-TKIs have been reviewed elsewhere and will not be discussed. We will focus on the mechanism of ifrst generation ALK TKI （crizotinib） resistance in patients with ALK positive NSCLC. Likewise, we will also discuss the current therapies for ALK positive NSCLC patients atfer crizotinib resistance.