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

Carmen Oi Ning Leung, Yang Yang, Rainbow Wing Hei Leung, Karl Kam Hei So, Hai Jun Guo, Martina Mang Leng Lei, Gregory Kenneth Muliawan, Yuan Gao, Qian Qian Yu, Jing Ping Yun, Stephanie Ma, Qian Zhao () and Terence Kin Wah Lee ()
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Carmen Oi Ning Leung: The Hong Kong Polytechnic University
Yang Yang: The Hong Kong Polytechnic University
Rainbow Wing Hei Leung: The Hong Kong Polytechnic University
Karl Kam Hei So: The Chinese University of Hong Kong
Hai Jun Guo: The Hong Kong Polytechnic University
Martina Mang Leng Lei: The Hong Kong Polytechnic University
Gregory Kenneth Muliawan: The Hong Kong Polytechnic University
Yuan Gao: Fourth Military Medical University
Qian Qian Yu: Huazhong University of Science and Technology
Jing Ping Yun: Sun Yat-Sen University Cancer Center
Stephanie Ma: The University of Hong Kong
Qian Zhao: The Hong Kong Polytechnic University
Terence Kin Wah Lee: The Hong Kong Polytechnic University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42360-w

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