https://scholars.lib.ntu.edu.tw/handle/123456789/597091
標題: | Heterogeneity of resistance mutations detectable by nextgeneration sequencing in TKI-treated lung adenocarcinoma | 作者: | Belchis D.A. LI-HUI TSENG Gniadek T. Haley L. Lokhandwala P. Illei P. Gocke C.D. Forde P. Brahmer J. Askin F.B. Eshleman J.R. Lin M.-T. |
關鍵字: | EGFR; Lung cancer; Next generation sequencing; PIK3CA; Tyrosine kinase resistance | 公開日期: | 2016 | 出版社: | Impact Journals LLC | 卷: | 7 | 期: | 29 | 起(迄)頁: | 45237-45248 | 來源出版物: | Oncotarget | 摘要: | EGFR-mutated lung adenocarcinomas routinely develop resistance to tyrosine kinase inhibitors (TKI). To better characterize the relative frequencies of the resistance mechanisms, we analyzed 48 EGFR-mutated TKI-resistant specimens from 41 patients. Next generation sequencing of post-treatment specimens detected EGFR p.T790M in 31 (79%) of 39 patients, PIK3CA mutations in 10 (26%), EGFR p.S768_V769delinsIL in one, and KRAS p.G12C in one. Five PIK3CA mutations were outside of codons 542, 545, and 1047. Three of four pre-treatment specimens did not carry the PIK3CA mutation found in the post-treatment sample. Small cell carcinoma transformation was identified in four patients; none had p.T790M, including two where p.T790M was identified in the co-existing adenocarcinoma. In p.T790M-mutated specimens, the allele frequency was less than 5% in 24% of cases. p.T790M allele frequency was usually lower than that of the sensitizing mutation indicating that the resistance mutation was present either in a subset of cells or, if the sensitizing mutation was amplified, in a subset of the sensitizing alleles of a dominant clone. Eight patients had multiple resistance mutations, suggesting either multiple separate resistant clones or a single clone harboring multiple resistance mechanisms. PIK3CA mutations appear to be a more significant resistance mechanism than previously recognized. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979941678&doi=10.18632%2foncotarget.9931&partnerID=40&md5=09f0979d8bef24937940410974242cd6 https://scholars.lib.ntu.edu.tw/handle/123456789/597091 |
ISSN: | 1949-2553 | DOI: | 10.18632/oncotarget.9931 | SDG/關鍵字: | epidermal growth factor receptor; erlotinib; gefitinib; protein tyrosine kinase inhibitor; epidermal growth factor receptor; KRAS protein, human; phosphatidylinositol 4,5 bisphosphate 3 kinase; PIK3CA protein, human; protein kinase inhibitor; protein p21; Article; cancer resistance; clinical article; codon; cohort analysis; controlled study; epidermal growth factor receptor gene; exon; gene; gene frequency; gene mutation; human; human tissue; lung adenocarcinoma; next generation sequencing; oncogene K ras; PIK3CA gene; retrospective study; single nucleotide polymorphism; small cell lung cancer; adenocarcinoma; drug resistance; genetics; high throughput sequencing; lung tumor; mutation; Adenocarcinoma; Class I Phosphatidylinositol 3-Kinases; Drug Resistance, Neoplasm; Gene Frequency; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Mutation; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Receptor, Epidermal Growth Factor |
顯示於: | 基因體暨蛋白體醫學研究所 |
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