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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

DC Field Value Language
dc.contributor.author김상우-
dc.contributor.author김성무-
dc.contributor.author김혜련-
dc.contributor.author이충근-
dc.contributor.author조병철-
dc.contributor.author양인석-
dc.date.accessioned2018-07-20T08:15:34Z-
dc.date.available2018-07-20T08:15:34Z-
dc.date.issued2017-
dc.identifier.issn0169-5002-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/161020-
dc.description.abstractOBJECTIVES: 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.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherElsevier Scientific Publishers-
dc.relation.isPartOfLUNG CANCER-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAdult-
dc.subject.MESHAged-
dc.subject.MESHCarcinoma, Non-Small-Cell Lung/drug therapy-
dc.subject.MESHCarcinoma, Non-Small-Cell Lung/genetics-
dc.subject.MESHCarcinoma, Non-Small-Cell Lung/pathology-
dc.subject.MESHDisease Progression-
dc.subject.MESHDrug Resistance, Neoplasm/drug effects-
dc.subject.MESHDrug Resistance, Neoplasm/genetics-
dc.subject.MESHFemale-
dc.subject.MESHGene Frequency-
dc.subject.MESHGenetic Heterogeneity-
dc.subject.MESHHigh-Throughput Nucleotide Sequencing/methods-
dc.subject.MESHHumans-
dc.subject.MESHLung Neoplasms/drug therapy-
dc.subject.MESHLung Neoplasms/genetics-
dc.subject.MESHLung Neoplasms/pathology-
dc.subject.MESHMale-
dc.subject.MESHMiddle Aged-
dc.subject.MESHMutation-
dc.subject.MESHProtein Kinase Inhibitors/therapeutic use-
dc.subject.MESHReceptor, Epidermal Growth Factor/antagonists & inhibitors-
dc.subject.MESHReceptor, Epidermal Growth Factor/drug effects-
dc.subject.MESHSurvival Analysis-
dc.titleNext-generation sequencing reveals novel resistance mechanisms and molecular heterogeneity in EGFR-mutant non-small cell lung cancer with acquired resistance to EGFR-TKIs-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Life Science-
dc.contributor.googleauthorChoong-kun Lee-
dc.contributor.googleauthorSora Kim-
dc.contributor.googleauthorJae Seok Lee-
dc.contributor.googleauthorJeong Eun Lee-
dc.contributor.googleauthorSung-moo Kim-
dc.contributor.googleauthorIn Seok Yang-
dc.contributor.googleauthorHye Ryun Kim-
dc.contributor.googleauthorJeong Ho Lee-
dc.contributor.googleauthorSangwoo Kim-
dc.contributor.googleauthorByoung Chul Cho-
dc.identifier.doi10.1016/j.lungcan.2017.09.005-
dc.contributor.localIdA00524-
dc.contributor.localIdA05094-
dc.contributor.localIdA01166-
dc.contributor.localIdA03259-
dc.contributor.localIdA03822-
dc.relation.journalcodeJ02174-
dc.identifier.eissn1872-8332-
dc.identifier.pmid29110836-
dc.identifier.urlhttps://www.sciencedirect.com/science/article/pii/S0169500217305044-
dc.subject.keywordEpidermal growth factor receptor-
dc.subject.keywordNext-generation sequencing-
dc.subject.keywordNon-small cell lung cancer-
dc.subject.keywordResistance mechanism-
dc.subject.keywordTyrosine kinase inhibitor-
dc.contributor.alternativeNameKim, Sang Woo-
dc.contributor.alternativeNameKim, Sung Moo-
dc.contributor.alternativeNameKim, Hye Ryun-
dc.contributor.alternativeNameLee, Choong Kun-
dc.contributor.alternativeNameCho, Byoung Chul-
dc.contributor.affiliatedAuthorKim, Sang Woo-
dc.contributor.affiliatedAuthorKim, Sung Moo-
dc.contributor.affiliatedAuthorKim, Hye Ryun-
dc.contributor.affiliatedAuthorLee, Choong Kun-
dc.contributor.affiliatedAuthorCho, Byoung Chul-
dc.citation.volume113-
dc.citation.startPage106-
dc.citation.endPage114-
dc.identifier.bibliographicCitationLUNG CANCER, Vol.113 : 106-114, 2017-
dc.identifier.rimsid60911-
dc.type.rimsART-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biomedical Systems Informatics (의생명시스템정보학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers

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