The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation of this pathway is a common mechanism in various cancers. Here, we report that CDK2 is a novel regulator of the ERK pathway via USP37 deubiquitinase (DUB). Mechanistically, CDK2 phosphorylates USP37, which is required for USP37 DUB activity. Further, USP37 deubiquitinates and stabilizes ERK1/2, thereby enhancing cancer cell proliferation. Thus, CDK2 is able to promote cell proliferation by activating USP37 and, in turn, stabilizing ERK1/2. Importantly, combined CDK1/2 and EGFR inhibitors have a synergetic anticancer effect through the downregulation of ERK1/2 stability and activity. Indeed, our patient-derived xenograft (PDX) results suggest that targeting both ERK1/2 stability and activity kills cancer cells more efficiently even at lower doses of these two inhibitors, which may reduce their associated side effects and indicate a potential new combination strategy for cancer therapy.
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November 13 2023
Synergistic anticancer effect by targeting CDK2 and EGFR–ERK signaling
Jinhuan Wu
,
Jinhuan Wu
*
(Conceptualization, Writing - original draft, Writing - review & editing)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
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Yuping Chen
,
Yuping Chen
*
(Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Writing - original draft, Writing - review & editing)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
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Rui Li
,
Rui Li
*
(Project administration, Validation)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
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Yaping Guan
,
Yaping Guan
(Formal analysis, Writing - review & editing)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
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Mu Chen
,
Mu Chen
(Validation, Visualization)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
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Hui Yin
,
Hui Yin
(Project administration, Visualization)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
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Xiaoning Yang
,
Xiaoning Yang
(Methodology, Writing - review & editing)
3School of Pharmacy,
Wenzhou Medical University
, Wenzhou, China
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Mingpeng Jin
,
Mingpeng Jin
(Data curation, Resources, Writing - original draft)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
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Bingsong Huang
,
Bingsong Huang
(Methodology)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
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Xin Ding
,
Xin Ding
(Project administration, Visualization)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
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Jie Yang
,
Jie Yang
(Investigation, Resources)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
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Zhe Wang
,
Zhe Wang
(Project administration, Visualization)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
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Yiming He
,
Yiming He
(Methodology)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
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Qianwen Wang
,
Qianwen Wang
(Project administration, Validation)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
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Jian Luo
,
Jian Luo
(Resources)
4Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center),
Tongji University School of Medicine
, Shanghai, China
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Ping Wang
,
Ping Wang
(Writing - review & editing)
5Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine,
Tongji University
, Shanghai, China
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Zhiyong Mao
,
Zhiyong Mao
(Investigation, Writing - review & editing)
6Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology,
Tongji University
, Shanghai, China
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Michael S.Y. Huen
,
Michael S.Y. Huen
(Supervision)
7School of Biomedical Sciences, LKS Faculty of Medicine,
The University of Hong Kong
, 21 Sassoon Road, Pokfulam, Hong Kong S.A.R.
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Zhenkun Lou
,
Zhenkun Lou
(Conceptualization)
8Department of Molecular Pharmacology and Experimental Therapeutics,
Mayo Clinic
, Rochester, MN, USA
9Department of Oncology,
Mayo Clinic
, Rochester, MN, USA
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Jian Yuan
,
(Conceptualization, Funding acquisition, Project administration, Supervision, Validation, Writing - review & editing)
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
Correspondence to Jian Yuan: yuanjian229@hotmail.com
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Fanghua Gong
3School of Pharmacy,
Wenzhou Medical University
, Wenzhou, China
Fanghua Gong: gongwenheng@163.com
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Jinhuan Wu
Conceptualization, Writing - original draft, Writing - review & editing
*
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
Yuping Chen
Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Writing - original draft, Writing - review & editing
*
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
Yaping Guan
Formal analysis, Writing - review & editing
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
Mu Chen
Validation, Visualization
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
Hui Yin
Project administration, Visualization
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
Xiaoning Yang
Methodology, Writing - review & editing
3School of Pharmacy,
Wenzhou Medical University
, Wenzhou, China
Mingpeng Jin
Data curation, Resources, Writing - original draft
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
Bingsong Huang
Methodology
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
Xin Ding
Project administration, Visualization
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
Jie Yang
Investigation, Resources
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
Zhe Wang
Project administration, Visualization
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
Yiming He
Methodology
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
Qianwen Wang
Project administration, Validation
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
Jian Luo
Resources
4Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center),
Tongji University School of Medicine
, Shanghai, China
Ping Wang
Writing - review & editing
5Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine,
Tongji University
, Shanghai, China
Zhiyong Mao
Investigation, Writing - review & editing
6Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology,
Tongji University
, Shanghai, China
Michael S.Y. Huen
Supervision
7School of Biomedical Sciences, LKS Faculty of Medicine,
The University of Hong Kong
, 21 Sassoon Road, Pokfulam, Hong Kong S.A.R.
Zhenkun Lou
Conceptualization
8Department of Molecular Pharmacology and Experimental Therapeutics,
Mayo Clinic
, Rochester, MN, USA
9Department of Oncology,
Mayo Clinic
, Rochester, MN, USA
Jian Yuan
Conceptualization, Funding acquisition, Project administration, Supervision, Validation, Writing - review & editing
1Research Center for Translational Medicine, East Hospital,
Tongji University School of Medicine
, Shanghai, China
2Department of Biochemistry and Molecular Biology,
Tongji University School of Medicine
, Shanghai, China
Correspondence to Jian Yuan: yuanjian229@hotmail.com
Fanghua Gong: gongwenheng@163.com
*
J. Wu, Y. Chen, and R. Li contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
March 02 2022
Revision Received:
April 05 2023
Accepted:
June 26 2023
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
National Key R&D Program of China
- Award Id(s): 2022YFA1302803
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 82002985,82172994,82225035,32090032,32070713
Funder(s):
Shanghai Pujiang program
- Award Id(s): 2020PJD070
Funder(s):
China Postdoctoral Science Foundation
- Award Id(s): 2020M681384
Funder(s):
Natural Science Foundation of Shanghai Municipality
- Award Id(s): 22XD1422300
Funder(s):
Shanghai Municipal Health Commission
- Award Id(s): 2022XD053
Funder(s):
Chinese Academy of Medical Sciences
- Award Id(s): 2019-I2M-5-028
© 2023 Wu et al.
2023
Wu et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2024) 223 (1): e202203005.
Article history
Received:
March 02 2022
Revision Received:
April 05 2023
Accepted:
June 26 2023
Citation
Jinhuan Wu, Yuping Chen, Rui Li, Yaping Guan, Mu Chen, Hui Yin, Xiaoning Yang, Mingpeng Jin, Bingsong Huang, Xin Ding, Jie Yang, Zhe Wang, Yiming He, Qianwen Wang, Jian Luo, Ping Wang, Zhiyong Mao, Michael S.Y. Huen, Zhenkun Lou, Jian Yuan, Fanghua Gong; Synergistic anticancer effect by targeting CDK2 and EGFR–ERK signaling. J Cell Biol 1 January 2024; 223 (1): e202203005. doi: https://doi.org/10.1083/jcb.202203005
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