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

Autor: Jieun Lee, Ahyoung Choi, Sung‐Yup Cho, Yukyung Jun, Deukchae Na, Ahra Lee, Giyong Jang, Jee Young Kwon, Jaesang Kim, Sanghyuk Lee, Charles Lee
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Molecular Oncology, Vol 15, Iss 2, Pp 487-502 (2021)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.12853
Popis: 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.
Databáze: Directory of Open Access Journals
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