Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance

Abstract Lenvatinib is the first target drug approved for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common, and the mechanisms of lenvatinib resistance and resistant targets in HCC are poorly understood. By using CRISPR/Cas9 library screening, we screene...

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Autores principales:	Yonggang Lu, Haoming Shen, Wenjie Huang, Sha He, Jianlin Chen, Di Zhang, Yongqi Shen, Yifan Sun
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/3fda2f305bd648cd807dee2f0ef61d95
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spelling	oai:doaj.org-article:3fda2f305bd648cd807dee2f0ef61d952021-11-21T12:08:49ZGenome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance10.1038/s41420-021-00747-y2058-7716https://doaj.org/article/3fda2f305bd648cd807dee2f0ef61d952021-11-01T00:00:00Zhttps://doi.org/10.1038/s41420-021-00747-yhttps://doaj.org/toc/2058-7716Abstract Lenvatinib is the first target drug approved for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common, and the mechanisms of lenvatinib resistance and resistant targets in HCC are poorly understood. By using CRISPR/Cas9 library screening, we screened out two key resistance genes, neurofibromin 1(NF1), and dual specificity phosphatase 9 (DUSP9), as critical drivers for lenvatinib resistance in HCC. With RNAi knockdown and CRISPR/Cas9 knockout models, we further clarified the mechanisms by which NF1 loss reactivates the PI3K/AKT and MAPK/ERK signaling pathways, while DUSP9 loss activates the MAPK/ERK signaling pathways, thereby inactivating FOXO3, followed by degradation of FOXO3, finally induced lenvatinib resistance. We also screened out trametinib, a small molecule pathway inhibitor for MEK, that can be used to reverse resistance induced by NF1 and DUSP9 loss in HCC cells. Trametinib was still able to halt HCC growth even when NF1 was knocked out in mice. Collectively, the findings indicate that NF1 and DUSP9 takes critical role in lenvatinib resistance and may be novel specific targets and predictive markers for lenvatinib resistance in HCC.Yonggang LuHaoming ShenWenjie HuangSha HeJianlin ChenDi ZhangYongqi ShenYifan SunNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCell Death Discovery, Vol 7, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 Yonggang Lu Haoming Shen Wenjie Huang Sha He Jianlin Chen Di Zhang Yongqi Shen Yifan Sun Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance
description	Abstract Lenvatinib is the first target drug approved for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common, and the mechanisms of lenvatinib resistance and resistant targets in HCC are poorly understood. By using CRISPR/Cas9 library screening, we screened out two key resistance genes, neurofibromin 1(NF1), and dual specificity phosphatase 9 (DUSP9), as critical drivers for lenvatinib resistance in HCC. With RNAi knockdown and CRISPR/Cas9 knockout models, we further clarified the mechanisms by which NF1 loss reactivates the PI3K/AKT and MAPK/ERK signaling pathways, while DUSP9 loss activates the MAPK/ERK signaling pathways, thereby inactivating FOXO3, followed by degradation of FOXO3, finally induced lenvatinib resistance. We also screened out trametinib, a small molecule pathway inhibitor for MEK, that can be used to reverse resistance induced by NF1 and DUSP9 loss in HCC cells. Trametinib was still able to halt HCC growth even when NF1 was knocked out in mice. Collectively, the findings indicate that NF1 and DUSP9 takes critical role in lenvatinib resistance and may be novel specific targets and predictive markers for lenvatinib resistance in HCC.
format	article
author	Yonggang Lu Haoming Shen Wenjie Huang Sha He Jianlin Chen Di Zhang Yongqi Shen Yifan Sun
author_facet	Yonggang Lu Haoming Shen Wenjie Huang Sha He Jianlin Chen Di Zhang Yongqi Shen Yifan Sun
author_sort	Yonggang Lu
title	Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance
title_short	Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance
title_full	Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance
title_fullStr	Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance
title_full_unstemmed	Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance
title_sort	genome-scale crispr-cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/3fda2f305bd648cd807dee2f0ef61d95
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Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance

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