BRAF mutations drive initiation and progression of various tumors. While BRAF inhibitors are effective in BRAF-mutant melanoma patients, intrinsic or acquired resistance to these therapies is common. Here, we identify non–receptor-type protein tyrosine phosphatase 23 (PTPN23) as an alternative effective target in BRAF-mutant cancer cells. Silencing PTPN23 selectively kills BRAF-mutant melanoma cells but not those with wild-type BRAF. Mechanistically, PTPN23, a catalytically inactive phosphatase, intriguingly induces WNK3-mediated phosphorylation of phosphoinositide 3-kinase class II alpha (PI3KC2α) at serine 329, enhancing its catalytic activity. This activation promotes production of PI(3,4)P2 and subsequent AKT2 activation at endosomes to support cell survival. Genetic or pharmacological targeting of the PTPN23-PI3KC2α-AKT2 signaling axis, alone or in combination with BRAF inhibitors, effectively inhibits the growth of BRAF-mutant melanoma and other cancers in vitro and in vivo. We also demonstrate that melanocyte-specific knockout of PTPN23 significantly inhibits BRAFV600E-driven melanomagenesis. Altogether, our findings demonstrate that targeting PTPN23/PI3KC2α offers a new and viable therapeutic strategy for BRAF-mutant cancers.
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January 22 2025
PTPN23-dependent activation of PI3KC2α is a therapeutic vulnerability of BRAF-mutant cancers
Ying He
,
Ying He
*
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
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Wei Li
,
Wei Li
*
(Data curation, Formal analysis, Investigation)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
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Meiling Zhang
,
Meiling Zhang
*
(Data curation, Formal analysis, Software, Visualization, Writing - review & editing)
2
Medical Research Institute, Guangdong Provincial People’s Hospital, Southern Medical University
, Guangzhou, China
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Hui Wang
,
Hui Wang
(Methodology, Resources)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
3
Shenzhen Medical Academy of Research and Translation (SMART)
, Shenzhen, China
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Peilu Lin
,
Peilu Lin
(Data curation, Formal analysis)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
4
School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School
, Shenzhen, China
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Ying Yu
,
Ying Yu
(Investigation)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
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Bin Huang
,
Bin Huang
(Investigation, Methodology)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
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Meng Hao
,
Meng Hao
(Investigation, Methodology)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
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Jianuo He
,
Jianuo He
(Formal analysis)
5
National Key Laboratory for Novel Software Technology, Nanjing University
, Nanjing, China
6
School of Artificial Intelligence, Nanjing University
, Nanjing, China
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Weiyao Kong
,
Weiyao Kong
(Investigation, Methodology)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
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Dan Luo
,
Dan Luo
(Investigation, Methodology)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
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Tengteng Xu
,
Tengteng Xu
(Investigation)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
3
Shenzhen Medical Academy of Research and Translation (SMART)
, Shenzhen, China
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Jiaqi Wang
,
Jiaqi Wang
(Data curation)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
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Ying Huang
,
Ying Huang
(Investigation, Methodology)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
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Qinwen Zhao
,
Qinwen Zhao
(Investigation)
7Department of Liver Surgery,
Center of Hepato-Pancreato-Biliary Surgery, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University
, Guangzhou, China
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Ying Liu
,
Ying Liu
(Investigation)
7Department of Liver Surgery,
Center of Hepato-Pancreato-Biliary Surgery, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University
, Guangzhou, China
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Jie Zhang
,
Jie Zhang
(Methodology, Software, Validation, Visualization, Writing - original draft)
5
National Key Laboratory for Novel Software Technology, Nanjing University
, Nanjing, China
6
School of Artificial Intelligence, Nanjing University
, Nanjing, China
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Yong Nian
,
Yong Nian
(Resources)
8
College of Pharmacy, Nanjing University of Chinese Medicine
, Nanjing, China
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Lei Zhang
,
Lei Zhang
(Formal analysis, Funding acquisition, Writing - review & editing)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
3
Shenzhen Medical Academy of Research and Translation (SMART)
, Shenzhen, China
4
School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School
, Shenzhen, China
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Bo Zhu
,
(Conceptualization, Funding acquisition, Resources, Writing - original draft, Writing - review & editing)
7Department of Liver Surgery,
Center of Hepato-Pancreato-Biliary Surgery, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University
, Guangzhou, China
Bo Zhu: [email protected]
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Chengqian Yin
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing)
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
3
Shenzhen Medical Academy of Research and Translation (SMART)
, Shenzhen, China
Correspondence to Chengqian Yin: [email protected]
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Ying He
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing
*
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
Meiling Zhang
Data curation, Formal analysis, Software, Visualization, Writing - review & editing
*
2
Medical Research Institute, Guangdong Provincial People’s Hospital, Southern Medical University
, Guangzhou, China
Hui Wang
Methodology, Resources
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
3
Shenzhen Medical Academy of Research and Translation (SMART)
, Shenzhen, China
Peilu Lin
Data curation, Formal analysis
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
4
School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School
, Shenzhen, China
Ying Yu
Investigation
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
Bin Huang
Investigation, Methodology
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
Meng Hao
Investigation, Methodology
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
Jianuo He
Formal analysis
5
National Key Laboratory for Novel Software Technology, Nanjing University
, Nanjing, China
6
School of Artificial Intelligence, Nanjing University
, Nanjing, China
Weiyao Kong
Investigation, Methodology
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
Dan Luo
Investigation, Methodology
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
Tengteng Xu
Investigation
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
3
Shenzhen Medical Academy of Research and Translation (SMART)
, Shenzhen, China
Jiaqi Wang
Data curation
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
Ying Huang
Investigation, Methodology
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
Qinwen Zhao
Investigation
7Department of Liver Surgery,
Center of Hepato-Pancreato-Biliary Surgery, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University
, Guangzhou, China
Ying Liu
Investigation
7Department of Liver Surgery,
Center of Hepato-Pancreato-Biliary Surgery, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University
, Guangzhou, China
Jie Zhang
Methodology, Software, Validation, Visualization, Writing - original draft
5
National Key Laboratory for Novel Software Technology, Nanjing University
, Nanjing, China
6
School of Artificial Intelligence, Nanjing University
, Nanjing, China
Yong Nian
Resources
8
College of Pharmacy, Nanjing University of Chinese Medicine
, Nanjing, China
Lei Zhang
Formal analysis, Funding acquisition, Writing - review & editing
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
3
Shenzhen Medical Academy of Research and Translation (SMART)
, Shenzhen, China
4
School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School
, Shenzhen, China
Bo Zhu
Conceptualization, Funding acquisition, Resources, Writing - original draft, Writing - review & editing
7Department of Liver Surgery,
Center of Hepato-Pancreato-Biliary Surgery, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University
, Guangzhou, China
Chengqian Yin
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
1
Institute of Cancer Research, Shenzhen Bay Laboratory
, Shenzhen, China
3
Shenzhen Medical Academy of Research and Translation (SMART)
, Shenzhen, China
Correspondence to Chengqian Yin: [email protected]
Bo Zhu: [email protected]
*
Y. He, W. Li, and M. Zhang contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
July 04 2024
Revision Received:
November 18 2024
Accepted:
December 11 2024
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funding
Funder(s):
National Key R&D Program of China
- Award Id(s): 2022YFA0912600
Funder(s):
Shenzhen Medical Research Fund
- Award Id(s): B2302018
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 32100579,82341011,82373179,82303061
Funder(s):
Shenzhen Bay Laboratory
- Award Id(s): SZBL2021080601004,S201101004
© 2025 He et al.
2025
He et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Exp Med (2025) 222 (3): e20241147.
Article history
Received:
July 04 2024
Revision Received:
November 18 2024
Accepted:
December 11 2024
Citation
Ying He, Wei Li, Meiling Zhang, Hui Wang, Peilu Lin, Ying Yu, Bin Huang, Meng Hao, Jianuo He, Weiyao Kong, Dan Luo, Tengteng Xu, Jiaqi Wang, Ying Huang, Qinwen Zhao, Ying Liu, Jie Zhang, Yong Nian, Lei Zhang, Bo Zhu, Chengqian Yin; PTPN23-dependent activation of PI3KC2α is a therapeutic vulnerability of BRAF-mutant cancers. J Exp Med 3 March 2025; 222 (3): e20241147. doi: https://doi.org/10.1084/jem.20241147
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