A Combinatorial CRISPR-Cas9 Screen Identifies Ifenprodil as an Adjunct to Sorafenib for Liver Cancer Treatment.

Autor:	Xu F; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Tong M; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.; State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Tong CSW; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Chan BKC; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Chu HY; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Wong TL; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Fong JHC; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Cheung MSH; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Mak KH; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Pardeshi L; Faculty of Health Sciences, University of Macau, Macau SAR, China.; Genomics and Bioinformatics Core, Faculty of Health Sciences, University of Macau, Macau SAR, China., Huang Y; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.; Department of Statistics and Actuarial Science, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Wong KH; Faculty of Health Sciences, University of Macau, Macau SAR, China.; Institute of Translational Medicine, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China.; MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China., Choi GCG; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Ma S; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. aslw@hku.hk stefma@hku.hk.; The University of Hong Kong-Shenzhen Hospital, Shenzhen, China., Wong ASL; Laboratory of Combinatorial Genetics and Synthetic Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. aslw@hku.hk stefma@hku.hk.; Department of Electrical and Electronic Engineering, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Dec 15; Vol. 81 (24), pp. 6219-6232. Date of Electronic Publication: 2021 Oct 19.
DOI:	10.1158/0008-5472.CAN-21-1017
Abstrakt:	Systematic testing of existing drugs and their combinations is an attractive strategy to exploit approved drugs for repurposing and identifying the best actionable treatment options. To expedite the search among many possible drug combinations, we designed a combinatorial CRISPR-Cas9 screen to inhibit druggable targets. Coblockade of the N-methyl-d-aspartate receptor (NMDAR) with targets of first-line kinase inhibitors reduced hepatocellular carcinoma (HCC) cell growth. Clinically, HCC patients with low NMDAR1 expression showed better survival. The clinically approved NMDAR antagonist ifenprodil synergized with sorafenib to induce the unfolded protein response, trigger cell-cycle arrest, downregulate genes associated with WNT signaling and stemness, and reduce self-renewal ability of HCC cells. In multiple HCC patient-derived organoids and human tumor xenograft models, the drug combination, but neither single drug alone, markedly reduced tumor-initiating cancer cell frequency. Because ifenprodil has an established safety history for its use as a vasodilator in humans, our findings support the repurposing of this drug as an adjunct for HCC treatment to improve clinical outcome and reduce tumor recurrence. These results also validate an approach for readily discovering actionable combinations for cancer therapy. SIGNIFICANCE: Combinatorial CRISPR-Cas9 screening identifies actionable targets for HCC therapy, uncovering the potential of combining the clinically approved drugs ifenprodil and sorafenib as a new effective treatment regimen. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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