Genome‐scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib‐resistant lung cancer
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 assoc...
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Online Access: | https://doi.org/10.1002/1878-0261.12853 |
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doaj-4e28d58fc3fe48a6a37f1e404bcd6ed32021-02-04T03:25:42ZengWileyMolecular Oncology1574-78911878-02612021-02-0115248750210.1002/1878-0261.12853Genome‐scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib‐resistant lung cancerJieun Lee0Ahyoung Choi1Sung‐Yup Cho2Yukyung Jun3Deukchae Na4Ahra Lee5Giyong Jang6Jee Young Kwon7Jaesang Kim8Sanghyuk Lee9Charles Lee10Department of Life Science Ewha Womans University Seoul KoreaDepartment of Bio‐Information Science Ewha Womans University Seoul KoreaDepartment of Biochemistry and Molecular Biology Seoul National University College of Medicine Seoul KoreaEwha‐JAX Cancer Immunotherapy Research Center, Ewha Womans University Seoul KoreaEwha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital Seoul KoreaEwha‐JAX Cancer Immunotherapy Research Center, Ewha Womans University Seoul KoreaDepartment of Life Science Ewha Womans University Seoul KoreaEwha‐JAX Cancer Immunotherapy Research Center, Ewha Womans University Seoul KoreaDepartment of Life Science Ewha Womans University Seoul KoreaDepartment of Life Science Ewha Womans University Seoul KoreaDepartment of Life Science Ewha Womans University Seoul KoreaErlotinib 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.https://doi.org/10.1002/1878-0261.12853cell cycle processCRISPR/Cas9 screeningerlotinib resistancelung cancerprotein ubiquitination pathway |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jieun Lee Ahyoung Choi Sung‐Yup Cho Yukyung Jun Deukchae Na Ahra Lee Giyong Jang Jee Young Kwon Jaesang Kim Sanghyuk Lee Charles Lee |
spellingShingle |
Jieun Lee Ahyoung Choi Sung‐Yup Cho Yukyung Jun Deukchae Na Ahra Lee Giyong Jang Jee Young Kwon Jaesang Kim Sanghyuk Lee Charles Lee Genome‐scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib‐resistant lung cancer Molecular Oncology cell cycle process CRISPR/Cas9 screening erlotinib resistance lung cancer protein ubiquitination pathway |
author_facet |
Jieun Lee Ahyoung Choi Sung‐Yup Cho Yukyung Jun Deukchae Na Ahra Lee Giyong Jang Jee Young Kwon Jaesang Kim Sanghyuk Lee Charles Lee |
author_sort |
Jieun Lee |
title |
Genome‐scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib‐resistant lung cancer |
title_short |
Genome‐scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib‐resistant lung cancer |
title_full |
Genome‐scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib‐resistant lung cancer |
title_fullStr |
Genome‐scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib‐resistant lung cancer |
title_full_unstemmed |
Genome‐scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib‐resistant lung cancer |
title_sort |
genome‐scale crispr screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib‐resistant lung cancer |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2021-02-01 |
description |
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. |
topic |
cell cycle process CRISPR/Cas9 screening erlotinib resistance lung cancer protein ubiquitination pathway |
url |
https://doi.org/10.1002/1878-0261.12853 |
work_keys_str_mv |
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