Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma
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 h...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42360-w |
| _version_ | 1827709770396598272 |
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| author | 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 Terence Kin Wah Lee |
| author_facet | 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 Terence Kin Wah Lee |
| author_sort | Carmen Oi Ning Leung |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:26:38Z |
| format | Article |
| id | doaj.art-a856563b24ce4b1ea218f1222a27a71c |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:26:38Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-a856563b24ce4b1ea218f1222a27a71c2023-11-20T10:09:11ZengNature PortfolioNature Communications2041-17232023-10-0114112010.1038/s41467-023-42360-wBroad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinomaCarmen Oi Ning Leung0Yang Yang1Rainbow Wing Hei Leung2Karl Kam Hei So3Hai Jun Guo4Martina Mang Leng Lei5Gregory Kenneth Muliawan6Yuan Gao7Qian Qian Yu8Jing Ping Yun9Stephanie Ma10Qian Zhao11Terence Kin Wah Lee12Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversitySchool of Biomedical Sciences, The Chinese University of Hong KongDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityState Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical UniversityDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathology, Sun Yat-Sen University Cancer CenterSchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniversityAbstract 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.https://doi.org/10.1038/s41467-023-42360-w |
| spellingShingle | 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 Terence Kin Wah Lee Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma Nature Communications |
| title | Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma |
| title_full | Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma |
| title_fullStr | Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma |
| title_full_unstemmed | Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma |
| title_short | Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma |
| title_sort | broad spectrum kinome profiling identifies cdk6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma |
| url | https://doi.org/10.1038/s41467-023-42360-w |
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