奥希替尼在非小细胞肺癌中的耐药机制及治疗策略

Drug-resistance mechanisms of non-small cell lung cancer to osimertinib and its potent treatment strategies

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)用于治疗存在表皮生长因子受体(epidermal growth factor receptor,EGFR)突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者,其第1代和第2代药物已取得明显疗效。奥希替尼(osimertinib)为第3代EGFR-TKIs,虽然对耐受第1代EGFR-TKIs的患者有较好疗效,但临床治疗结果表明其可诱导产生耐药性,目前临床尚无有效的应对方法,这已成为治疗EGFR阳性NSCLC的主要障碍之一。目前已有研究发现,奥希替尼可诱导MET和BIM等基因突变,从而产生耐药性。针对这些基因突变位点进行的药物联合治疗可能对克服耐药有效,进一步研究奥希替尼耐药性产生的具体机制对指导临床应对耐药有重要意义。

Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs) have been used in the treatment of patients with non-small cell lung cancer(NSCLC) and epidermal growth factor receptor(EGFR) gene mutations. The first and second-generation of EGFR-TKIs have achieved significant results. Osimertinib is one of the third-generation of EGFR-TKIs that has good effects in the patients with the resistance to first-generation of EGFR-TKIs. However, the clinical treatment results show that osimertinib can induce drug resistance. At present, no effective solution has been developed for the drug resistance in clinical application of osimertinib, which has become one of the major obstacles in the treatment of EGFR-positive NSCLC. It has been found that osimertinib treatment can induce the mutations of MET, BIM and other genes, which results in drug resistance of tumor. This drug-resistance can likely be overcome using combination therapies that are targeted to these gene mutation sites. Further studies on the mechanism of resistance to osimertinib will be of great significance in guiding the clinical response to the occurrence of drug resistance.