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Next-generation sequencing reveals novel resistance mechanisms and molecular heterogeneity in EGFR-mutant non-small cell lung cancer with acquired resistance to EGFR-TKIs

 Choong-kun Lee  ;  Sora Kim  ;  Jae Seok Lee  ;  Jeong Eun Lee  ;  Sung-moo Kim  ;  In Seok Yang  ;  Hye Ryun Kim  ;  Jeong Ho Lee  ;  Sangwoo Kim  ;  Byoung Chul Cho 
 LUNG CANCER, Vol.113 : 106-114, 2017 
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Adult ; Aged ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Disease Progression ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Female ; Gene Frequency ; Genetic Heterogeneity ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Male ; Middle Aged ; Mutation ; Protein Kinase Inhibitors/therapeutic use ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Receptor, Epidermal Growth Factor/drug effects ; Survival Analysis
Epidermal growth factor receptor ; Next-generation sequencing ; Non-small cell lung cancer ; Resistance mechanism ; Tyrosine kinase inhibitor
OBJECTIVES: Despite initial responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant non-small cell lung cancer, patients invariably develop acquired resistance. In this study, we performed next-generation sequencing in pre- and post-EGFR-TKI tumor samples to identify novel resistance mechanisms to EGFR-TKIs. MATERIAL AND METHODS: We collected tumor tissues before EGFR-TKI treatment and after progression from 19 NSCLC patients to analyze genomic alterations in 409 cancer related genes. Bioinformatics analyses were used to identify mutations in which the allele frequencies are significantly changed, or newly appeared after progression. RESULTS: Overall, mutation rates and compositions were similar between pre- and post-EGFR-TKI tumors. We identified EGFR T790M as the most common mechanism of acquired resistance (63.2%). No pre-EGFR-TKI tumor had a preexisting T790M mutation, suggesting that tumors acquired T790M mutations following progression on EGFR-TKIs. Compared to T790M-positive tumors, T790M-negative tumors showed relatively high tumor mutation burden and shorter survival, suggesting T790M-negative patients as a potential candidate for immune checkpoint inhibitors. TP53 mutation was also significantly enriched in the T790M-negative tumors. Finally, we described here for the first time a novel missense mutation (T263P), which occurred concurrently with an activating G719A mutation, in the extracellular domain II of EGFR in a patient with poor response to erlotinib. Ba/F3 cells harboring EGFR T263P/G719A mutation showed higher sensitivity to afatinib, compared to gefitinib due to inhibition of EGFR/HER2 heterodimerization. CONCLUSION: Comprehensive genomic analysis of post-EGFR-TKI tumors can provide novel insight into the complex molecular mechanisms of acquired resistance to EGFR-TKIs.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sangwoo(김상우) ORCID logo https://orcid.org/0000-0001-5356-0827
Kim, Sung Moo(김성무)
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Yang, In Seok(양인석) ORCID logo https://orcid.org/0000-0001-5224-2587
Lee, Choong Kun(이충근)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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