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Genome-scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib-resistant lung cancer

Title
Genome-scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib-resistant lung cancer
Authors
Lee J.Choi A.Cho S.-Y.Jun Y.Na D.Lee A.Jang G.Kwon J.Y.Kim J.Lee S.Lee C.
Ewha Authors
이상혁김재상Charles Lee장기용이지은
SCOPUS Author ID
이상혁scopus; 김재상scopus; Charles Leescopus
Issue Date
2021
Journal Title
Molecular Oncology
ISSN
1574-7891JCR Link
Citation
Molecular Oncology vol. 15, no. 2, pp. 487 - 502
Keywords
cell cycle processCRISPR/Cas9 screeningerlotinib resistancelung cancerprotein ubiquitination pathway
Publisher
John Wiley and Sons Ltd
Indexed
SCIE; SCOPUS scopus
Document Type
Article
Abstract
Erlotinib is highly effective in lung cancer patients with epidermal growth factor receptor (EGFR) mutations. However, despite initial favorable responses, most patients rapidly develop resistance to erlotinib soon after the initial treatment. This study aims to identify new genes and pathways associated with erlotinib resistance mechanisms in order to develop novel therapeutic strategies. Here, we induced knockout (KO) mutations in erlotinib-resistant human lung cancer cells (NCI-H820) using a genome-scale CRISPR-Cas9 sgRNA library to screen for genes involved in erlotinib susceptibility. The spectrum of sgRNAs incorporated among erlotinib-treated cells was substantially different to that of the untreated cells. Gene set analyses showed a significant depletion of ‘cell cycle process’ and ‘protein ubiquitination pathway’ genes among erlotinib-treated cells. Chemical inhibitors targeting genes in these two pathways, such as nutlin-3 and carfilzomib, increased cancer cell death when combined with erlotinib in both in vitro cell line and in vivo patient-derived xenograft experiments. Therefore, we propose that targeting cell cycle processes or protein ubiquitination pathways are promising treatment strategies for overcoming resistance to EGFR inhibitors in lung cancer. © 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
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DOI
10.1002/1878-0261.12853
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자연과학대학 > 생명과학전공 > Journal papers
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