Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma.

Autor: Leung CON; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China., Yang Y; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China., Leung RWH; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China., So KKH; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China., Guo HJ; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China., Lei MML; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China., Muliawan GK; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China., Gao Y; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'An, China., Yu QQ; Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Yun JP; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China., Ma S; School of Biomedical Sciences, 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., Zhao Q; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China. q.zhao@polyu.edu.hk.; Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong, China. q.zhao@polyu.edu.hk.; State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong, China. q.zhao@polyu.edu.hk., Lee TKW; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China. terence.kw.lee@polyu.edu.hk.; Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong, China. terence.kw.lee@polyu.edu.hk.; State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong, China. terence.kw.lee@polyu.edu.hk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Oct 23; Vol. 14 (1), pp. 6699. Date of Electronic Publication: 2023 Oct 23.
DOI: 10.1038/s41467-023-42360-w
Abstrakt: Increasing evidence has demonstrated that drug resistance can be acquired in cancer cells by kinase rewiring, which is an obstacle for efficient cancer therapy. However, it is technically challenging to measure the expression of protein kinases on large scale due to their dynamic range in human proteome. We employ a lysine-targeted sulfonyl fluoride probe, named XO44, which binds to 133 endogenous kinases in intact lenvatinib-resistant hepatocellular carcinoma (HCC) cells. This analysis reveals cyclin-dependent kinase 6 (CDK6) upregulation, which is mediated by ERK/YAP1 signaling cascade. Functional analyses show that CDK6 is crucial in regulation of acquired lenvatinib resistance in HCC via augmentation of liver cancer stem cells with clinical significance. We identify a noncanonical pathway of CDK6 in which it binds and regulates the activity of GSK3β, leading to activation of Wnt/β-catenin signaling. Consistently, CDK6 inhibition by palbociclib or degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with lenvatinib in vitro. Interestingly, palbociclib not only exerts maximal growth suppressive effect with lenvatinib in lenvatinib-resistant HCC models but also reshapes the tumor immune microenvironment. Together, we unveil CDK6 as a druggable target in lenvatinib-resistant HCC and highlight the use of a chemical biology approach to understand nongenetic resistance mechanisms in cancer.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: