TY  - JOUR
A1  - Jia, Peilin
A1  - Jin, Hailing
A1  - Meador, Catherine B.
A1  - Xia, Junfeng
A1  - Ohashi, Kadoaki
A1  - Liu, Lin
A1  - Pirazzoli, Valentina
A1  - Dahlman, Kimberly B.
A1  - Politi, Katerina
A1  - Michor, Franziska
A1  - Zhao, Zhongming
A1  - Pao, William
T1  - 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
Y1  - 2013/09/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1434 
EP  - 1445 
DO  - 10.1101/gr.152322.112 
VL  - 23 
IS  - 9 
UR  - http://genome.cshlp.org/content/23/9/1434.abstract 
N2  - Somatic mutations in kinase genes are associated with sensitivity of solid tumors to kinase inhibitors, but patients with metastatic cancer eventually develop disease progression. In EGFR mutant lung cancer, modeling of acquired resistance (AR) with drug-sensitive cell lines has identified clinically relevant EGFR tyrosine kinase inhibitor (TKI) resistance mechanisms such as the second-site mutation, EGFR T790M, amplification of the gene encoding an alternative kinase, MET, and epithelial–mesenchymal transition (EMT). The full spectrum of DNA changes associated with AR remains unknown. We used next-generation sequencing to characterize mutational changes associated with four populations of EGFR mutant drug-sensitive and five matched drug-resistant cell lines. Comparing resistant cells with parental counterparts, 18–91 coding SNVs/indels were predicted to be acquired and 1–27 were lost; few SNVs/indels were shared across resistant lines. Comparison of two related parental lines revealed no unique coding SNVs/indels, suggesting that changes in the resistant lines were due to drug selection. Surprisingly, we observed more CNV changes across all resistant lines, and the line with EMT displayed significantly higher levels of CNV changes than the other lines with AR. These results demonstrate a framework for studying the evolution of AR and provide the first genome-wide spectrum of mutations associated with the development of cellular drug resistance in an oncogene-addicted cancer. Collectively, the data suggest that CNV changes may play a larger role than previously appreciated in the acquisition of drug resistance and highlight that resistance may be heterogeneous in the context of different tumor cell backgrounds. 
ER  -