title: Mutational profiling of non-small-cell lung cancer patients resistant to first-generation EGFR tyrosine kinase inhibitors using next generation sequencing.
abstract: Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is secondary EGFR-T790M mutation. Other mechanisms, such as HER2 and MET amplifications, and PIK3CA mutations, were also reported. However, the mechanisms in the remaining patients are still unknown. In this study, we performed mutational profiling in a cohort of 83 NSCLC patients with TKI-sensitizing EGFR mutations at diagnosis and acquired resistance to three different first-generation EGFR TKIs using targeted next generation sequencing (NGS) of 416 cancer-related genes. In total, we identified 322 genetic alterations with a median of 3 mutations per patient. 61% of patients still exhibit TKI-sensitizing EGFR mutations, and 36% of patients acquired EGFR-T790M. Besides other known resistance mechanisms, we identified TET2 mutations in 12% of patients. Interestingly, we also observed SOX2 amplification in EGFR-T790M negative patients, which are restricted to Icotinib treatment resistance, a drug widely used in Chinese NSCLC patients. Our study uncovered mutational profiles of NSCLC patients with first-generation EGFR TKIs resistance with potential therapeutic implications.
authors.affiliation: Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China.|Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Geneseeq Technology Inc., Toronto, Ontario, Canada.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
authors.forename: Guangyuan
authors.initials: G
authors.lastname: Lou
authors.affiliation: Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Geneseeq Technology Inc., Toronto, Ontario, Canada.
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.affiliation: Geneseeq Technology Inc., Toronto, Ontario, Canada.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China.|Zhejiang Key Laboratory of Diagnosis and Treatment Technology of Thoracic Oncology, Hangzhou, China.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Yu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D015331:Cohort Studies; D043844:Crown Ethers / Q000494:pharmacology; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology
chemical_list: D043844:Crown Ethers; D011799:Quinazolines; C531470:icotinib; D066246:ErbB Receptors
keywords: drug resistance; epithelial growth factor receptor; next generation sequencing; non-small-cell lung cancer; tyrosine kinase inhibitor