基于液体活检与二代测序解析肺腺癌患者靶向药耐药机制

Deciphering Resistance Mechanism of Targeted Therapy in Lung Adenocarcinoma Patients Based on Liquid Biopsy and Next-generation Sequencing

表皮生长因子受体酪氨酸激酶抑制剂(EGFR TKI)是治疗非小细胞肺癌的一线药物,但在治疗过程中难以避免耐药性的产生。目前已知的获得性耐药机制主要包括EGFR T790M突变、HER2基因扩增、MET基因扩增、转分化等,并尚有15%~20%的患者的耐药机制不明。本研究发展了一种基于液体活检与高通量测序方式解析肺癌患者靶向药物耐药机制的方法。我们通过液体活检的方式取得了接受EGFR TKI治疗肺腺癌患者治疗前及EGFR TKI耐药后的胸腔积液样本,在对其中的肿瘤细胞进行富集后,通过基因组及转录组的高通量测序并结合生物信息学分析,解析耐药前、耐药后基因组变异以及基因表达的差异,进而探究该患者的靶向药物耐药机制,为制订新的治疗方案提供科学依据。

Epidermal growth factor receptor tyrosine kinase inhibitor(EGFR TKI)is the first-line treatment for non-small cell lung cancer,but it is difficult to avoid drug resistance during the therapy.A variety of TKI resistance mechanisms have been discovered,including EGFR T790M mutation,HER2 amplification,MET amplification and trans-differentiation,as well as 15%~20%of patients with unknown mechanisms of TKI resistance.In this study,we developed a method to resolve drug resistance mechanism of molecularly targeted therapy in lung adenocarcinoma patients based on liquid biopsy and high-throughput sequencing.We collected pleural effusion samples before the TKI therapy and after development of TKI resistance in a lung adenocarcinoma patient by liquid biopsy,followed by enrichment of tumor cells and high-throughput sequencing of whole exome and transcriptome.The sequencing results were analyzed to discover genomic and transcriptomic alternations after drug resistance for deciphering the resistance mechanism that paved the way for optimizing therapy.