Next-generation sequencing of paired tyrosine kinase inhibitor-sensitive and -resistant EGFR mutant lung cancer cell lines identifies spectrum of DNA changes associated with drug resistance.

摘要: Somatic mutations in kinase genes are associated with sensitivity of solid tumors to inhibitors, but patients metastatic cancer eventually develop disease progression. In EGFR mutant lung cancer, modeling acquired resistance (AR) drug-sensitive cell lines has identified clinically relevant tyrosine inhibitor (TKI) mechanisms such as the second-site mutation, T790M, amplification gene encoding an alternative kinase, MET, and epithelial-mesenchymal transition (EMT). The full spectrum DNA changes AR remains unknown. We used next-generation sequencing characterize mutational four populations five matched drug-resistant lines. Comparing resistant cells parental counterparts, 18-91 coding SNVs/indels were predicted be 1-27 lost; few shared across Comparison two related revealed no unique SNVs/indels, suggesting that due drug selection. Surprisingly, we observed more CNV all lines, line EMT displayed significantly higher levels than other AR. These results demonstrate a framework for studying evolution provide first genome-wide development cellular oncogene-addicted cancer. Collectively, data suggest may play larger role previously appreciated acquisition highlight heterogeneous context different tumor backgrounds.