Genome-wide CRISPR Screening Identifies NFκB and c-MET as Druggable Targets to Sensitize Lenvatinib Treatment in Hepatocellular CarcinomaSummary
Background & Aims: Hepatocellular carcinoma (HCC), the dominant form of liver cancer, is a leading cause of cancer death worldwide. Sorafenib and lenvatinib have long been the 2 limited options of first-line treatments for patients with unresectable advanced HCC. However, the single-drug tre...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X25000438 |
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| author | Ting-Chi Rebecca Wan Lai Wei Lai-Hung Cheng Wai-Ching Chin Jialing Shen For-Fan Chan Zhijian Kuang Cun Wang Carmen Chak-Lui Wong Chun-Ming Wong |
| author_facet | Ting-Chi Rebecca Wan Lai Wei Lai-Hung Cheng Wai-Ching Chin Jialing Shen For-Fan Chan Zhijian Kuang Cun Wang Carmen Chak-Lui Wong Chun-Ming Wong |
| author_sort | Ting-Chi Rebecca Wan |
| collection | DOAJ |
| description | Background & Aims: Hepatocellular carcinoma (HCC), the dominant form of liver cancer, is a leading cause of cancer death worldwide. Sorafenib and lenvatinib have long been the 2 limited options of first-line treatments for patients with unresectable advanced HCC. However, the single-drug treatment strategy only shows modest survival benefit, mostly because of the survival ability of cancer cells to activate alternative pathways for compensation. In this study, we aim to identify druggable targets contributing to lenvatinib resistance and evaluate the efficacy of combining respective inhibitors and lenvatinib on HCC. Methods: Genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 knockout library screening was applied on the vehicle group and lenvatinib treatment group. Identified druggable candidates were validated individually on HCC cell models. Therapeutic effects of the combined treatment of inhibitors of candidate genes and lenvatinib were evaluated in vitro and in vivo. Results: We successfully identified NFKB1 and MET as critical drivers for the development of lenvatinib resistance in HCC cells. By perturbing the 2 genes with either CRISPR knockout or RNA interference approaches, lenvatinib treatments were significantly sensitized. Moreover, using small molecules QNZ and cabozantinib to target NFKB1 and MET, respectively, this together with lenvatinib could synergistically induce apoptosis and suppress HCC growth in vitro and in vivo. Conclusion: Our results demonstrated that genome-wide CRISPR/Cas9 screening is a powerful tool for the design of rational combinational cancer therapy and provided candidate genes possible for combined treatments with lenvatinib to improve therapy efficacy. |
| format | Article |
| id | doaj-art-5efe9cba12fa4a5a867452cdfe6f42d1 |
| institution | OA Journals |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-5efe9cba12fa4a5a867452cdfe6f42d12025-08-20T01:50:49ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-0119710150210.1016/j.jcmgh.2025.101502Genome-wide CRISPR Screening Identifies NFκB and c-MET as Druggable Targets to Sensitize Lenvatinib Treatment in Hepatocellular CarcinomaSummaryTing-Chi Rebecca Wan0Lai Wei1Lai-Hung Cheng2Wai-Ching Chin3Jialing Shen4For-Fan Chan5Zhijian Kuang6Cun Wang7Carmen Chak-Lui Wong8Chun-Ming Wong9Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, ChinaDepartment of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, ChinaDepartment of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, ChinaDepartment of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, ChinaDepartment of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, ChinaDepartment of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, ChinaDepartment of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, ChinaState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, ChinaDepartment of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China; Correspondence Address correspondence to: Chun-Ming Wong, PhD, State Key Laboratory of Liver Research, Rm 711, No. 5 Sassoon Road, The University of Hong Kong, Hong Kong.Background & Aims: Hepatocellular carcinoma (HCC), the dominant form of liver cancer, is a leading cause of cancer death worldwide. Sorafenib and lenvatinib have long been the 2 limited options of first-line treatments for patients with unresectable advanced HCC. However, the single-drug treatment strategy only shows modest survival benefit, mostly because of the survival ability of cancer cells to activate alternative pathways for compensation. In this study, we aim to identify druggable targets contributing to lenvatinib resistance and evaluate the efficacy of combining respective inhibitors and lenvatinib on HCC. Methods: Genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 knockout library screening was applied on the vehicle group and lenvatinib treatment group. Identified druggable candidates were validated individually on HCC cell models. Therapeutic effects of the combined treatment of inhibitors of candidate genes and lenvatinib were evaluated in vitro and in vivo. Results: We successfully identified NFKB1 and MET as critical drivers for the development of lenvatinib resistance in HCC cells. By perturbing the 2 genes with either CRISPR knockout or RNA interference approaches, lenvatinib treatments were significantly sensitized. Moreover, using small molecules QNZ and cabozantinib to target NFKB1 and MET, respectively, this together with lenvatinib could synergistically induce apoptosis and suppress HCC growth in vitro and in vivo. Conclusion: Our results demonstrated that genome-wide CRISPR/Cas9 screening is a powerful tool for the design of rational combinational cancer therapy and provided candidate genes possible for combined treatments with lenvatinib to improve therapy efficacy.http://www.sciencedirect.com/science/article/pii/S2352345X25000438CabozantinibCRISPR Library ScreeningLenvatinibHCCMETNFKB1 |
| spellingShingle | Ting-Chi Rebecca Wan Lai Wei Lai-Hung Cheng Wai-Ching Chin Jialing Shen For-Fan Chan Zhijian Kuang Cun Wang Carmen Chak-Lui Wong Chun-Ming Wong Genome-wide CRISPR Screening Identifies NFκB and c-MET as Druggable Targets to Sensitize Lenvatinib Treatment in Hepatocellular CarcinomaSummary Cellular and Molecular Gastroenterology and Hepatology Cabozantinib CRISPR Library Screening Lenvatinib HCC MET NFKB1 |
| title | Genome-wide CRISPR Screening Identifies NFκB and c-MET as Druggable Targets to Sensitize Lenvatinib Treatment in Hepatocellular CarcinomaSummary |
| title_full | Genome-wide CRISPR Screening Identifies NFκB and c-MET as Druggable Targets to Sensitize Lenvatinib Treatment in Hepatocellular CarcinomaSummary |
| title_fullStr | Genome-wide CRISPR Screening Identifies NFκB and c-MET as Druggable Targets to Sensitize Lenvatinib Treatment in Hepatocellular CarcinomaSummary |
| title_full_unstemmed | Genome-wide CRISPR Screening Identifies NFκB and c-MET as Druggable Targets to Sensitize Lenvatinib Treatment in Hepatocellular CarcinomaSummary |
| title_short | Genome-wide CRISPR Screening Identifies NFκB and c-MET as Druggable Targets to Sensitize Lenvatinib Treatment in Hepatocellular CarcinomaSummary |
| title_sort | genome wide crispr screening identifies nfκb and c met as druggable targets to sensitize lenvatinib treatment in hepatocellular carcinomasummary |
| topic | Cabozantinib CRISPR Library Screening Lenvatinib HCC MET NFKB1 |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X25000438 |
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