非小细胞肺癌EGFR-TKIs耐药——小细胞肺癌转化的研究进展

Advances in the Transformation to Small Cell Lung Cancer from Non-small Cell Lung Cancer Following Acquired Drug-resistance to EGFR Tyrosine Kinase Inhibitors

表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors,EGFR TKIs)在治疗携带EGFR基因敏感突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)中已取得显著疗效,但是,耐药的产生几乎是不可避免的,常见的耐药机制包括T790M突变、cMET基因扩增等。目前已有文献报道EGFRTKI耐药的机制之一为NSCLC转化为小细胞肺癌(small cell lung cancer,SCLC),大约占3%-15%,是一种重要的少见耐药机制,并不为人们所深入了解。本文从"共同起源"和"转化时间节点"两个角度对其进行了归纳总结,重点探讨了其转化的可能机制,目前提出的两种可能转化机制分别为肿瘤异质性假说、NSCLC转化为SCLC假说,还涉及了许多分子水平的改变,如RB1基因缺失、P53基因失活、PTEN M264I基因突变等,同时对该种转化的发病特点、治疗策略等方面进行了归纳与总结。目前仍有许多问题需要进一步研究和解决。

The use of epidermal growth factor receptor tyrosine kinase inhibitors （EGFR-TKIs） in the treatment of sensitive EGFR mutation in non-small cell lung cancer （NSCLC） has been proved significant curative effect. However, the ac- quisition of the drug resistance to EGFR-TKIs is almost inevitable, and common drug resistance mechanisms include T790M mutation, cMET amplification, etc. One of the rare resistance mechanisms of EGFR-TKIs is the transformation from NSCLC into small cell lung cancer （SCLC）, which account for about 3%-15%. It is an important rare drug resistance mechanism which is not well understood. Therefore, it is necessary to review the present situation and the progress of the this drug resistance mechanism. This article summarizes these hypothesizes from two parts, which are respectively the ＂common origin＂ and ＂transformation time node＂. At present, two possible mechanisms of this kind of transformation has been proposed, which are respectively the hypothesis of the tumor heterogeneity and the hypothesis of the transformation from NSCLC into SCLC. This article also involves a lot of changes in the level of molecules, such as the lack ofRB1 gene, the inactivation ofP53 gene and the mutation of PTEN M264I gene, etc. At the same time, this article summarizes the characteristics, the diagnostic methods and the treatment strategy of this kind of transformation. There are still many problems which need further research and resolution.