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dc.contributor.author Jeong, Youngtae ko
dc.contributor.author Hellyer, Jessica A. ko
dc.contributor.author Stehr, Henning ko
dc.contributor.author Hoang, Ngoc T. ko
dc.contributor.author Niu, Xiaomin ko
dc.contributor.author Das, Millie ko
dc.contributor.author Padda, Sukhmani K. ko
dc.contributor.author Ramchandran, Kavitha ko
dc.contributor.author Neal, Joel W. ko
dc.contributor.author Wakelee, Heather ko
dc.contributor.author Diehn, Maximilian ko
dc.date.accessioned 2019-12-16T01:11:38Z -
dc.date.available 2019-12-16T01:11:38Z -
dc.date.created 2019-12-02 -
dc.date.issued 2020-01 -
dc.identifier.citation Clinical Cancer Research, v.26, no.1, pp.274 - 281 -
dc.identifier.issn 1078-0432 -
dc.identifier.uri http://hdl.handle.net/20.500.11750/10990 -
dc.description.abstract Purpose: Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations that activate NFE2L2, including mutations in NFE2L2, KEAP1, or CUL3, have been found to be associated with poor outcomes in patients with non–small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored. Experimental Design: We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 patients with stage IV NSCLC with KEAP1, NFE2L2, or CUL3 mutations and a matched cohort of 52 wild-type patients. Time to treatment failure after first-line platinum doublet chemotherapy and overall survival was compared between the two groups. Results: Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In patients with NSCLC, median time to treatment failure (TTF) after first-line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared with 8.3 months in the control group (P < 0.0001). Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (P ¼ 0.006). Conclusions: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter TTF and OS after first-line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of patients with NSCLC are therefore needed. ©2019 American Association for Cancer Research. -
dc.language English -
dc.publisher American Association for Cancer Research -
dc.title Role of KEAP1/NFE2L2 Mutations in the Chemotherapeutic Response of Patients with Non-Small Cell Lung Cancer. -
dc.type Article -
dc.identifier.doi 10.1158/1078-0432.CCR-19-1237 -
dc.identifier.wosid 000505668000030 -
dc.identifier.scopusid 2-s2.0-85077475455 -
dc.type.local Article(Overseas) -
dc.type.rims ART -
dc.description.journalClass 1 -
dc.contributor.nonIdAuthor Hellyer, Jessica A. -
dc.contributor.nonIdAuthor Stehr, Henning -
dc.contributor.nonIdAuthor Hoang, Ngoc T. -
dc.contributor.nonIdAuthor Niu, Xiaomin -
dc.contributor.nonIdAuthor Das, Millie -
dc.contributor.nonIdAuthor Padda, Sukhmani K. -
dc.contributor.nonIdAuthor Ramchandran, Kavitha -
dc.contributor.nonIdAuthor Neal, Joel W. -
dc.contributor.nonIdAuthor Wakelee, Heather -
dc.contributor.nonIdAuthor Diehn, Maximilian -
dc.identifier.citationVolume 26 -
dc.identifier.citationNumber 1 -
dc.identifier.citationStartPage 274 -
dc.identifier.citationEndPage 281 -
dc.identifier.citationTitle Clinical Cancer Research -
dc.type.journalArticle Article -
dc.description.isOpenAccess N -
dc.subject.keywordPlus OXIDATIVE STRESS -
dc.subject.keywordPlus ACTIVATES NRF2 -
dc.subject.keywordPlus CHEMORESISTANCE -
dc.subject.keywordPlus RESISTANCE -
dc.subject.keywordPlus INITIATION -
dc.subject.keywordPlus PROGNOSIS -
dc.subject.keywordPlus CARCINOMA -
dc.subject.keywordPlus FACTOR-2 -
dc.subject.keywordPlus EFFICACY -
dc.subject.keywordPlus GROWTH -
dc.contributor.affiliatedAuthor Jeong, Youngtae -
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Department of New Biology Lab of Stem Cell Biology & Cancer Precision Medicine 1. Journal Articles

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