DDR1/2 enhance KIT activation and imatinib resistance of primary and secondary KIT mutants in gastrointestinal stromal tumors
Anbu Liu
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorShaoting Zhang
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorMing Wang
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorLiangying Zhang
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorShidong Xu
Department of Oncology, School of Medicine, Tongren Hospital, Shanghai Jiao Tong University, Shanghai, China
Search for more papers by this authorAhmad Nasimian
Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, Lund, Sweden
Search for more papers by this authorShujing Li
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Department of Pediatrics, The General Hospital of Ningxia Medical University, Yinchuan, China
Search for more papers by this authorSien Zhao
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorXu Cao
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorJinhai Tian
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorYuanyuan Yu
Department of Emergency, The General Hospital of Ningxia Medical University, Yinchuan, China
Search for more papers by this authorZhaoyang Fan
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorKun Xiao
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorHui Zhao
Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Ministry of Education, The Chinese University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorCorresponding Author
Julhash U. Kazi
Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, Lund, Sweden
Correspondence Jianmin Sun
Email: [email protected]
Lijun Ma
Email: [email protected]
Julhash U. Kazi
Email: [email protected]
Search for more papers by this authorCorresponding Author
Lijun Ma
Department of Oncology, School of Medicine, Tongren Hospital, Shanghai Jiao Tong University, Shanghai, China
Correspondence Jianmin Sun
Email: [email protected]
Lijun Ma
Email: [email protected]
Julhash U. Kazi
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jianmin Sun
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Correspondence Jianmin Sun
Email: [email protected]
Lijun Ma
Email: [email protected]
Julhash U. Kazi
Email: [email protected]
Search for more papers by this authorAnbu Liu
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorShaoting Zhang
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorMing Wang
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorLiangying Zhang
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorShidong Xu
Department of Oncology, School of Medicine, Tongren Hospital, Shanghai Jiao Tong University, Shanghai, China
Search for more papers by this authorAhmad Nasimian
Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, Lund, Sweden
Search for more papers by this authorShujing Li
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Department of Pediatrics, The General Hospital of Ningxia Medical University, Yinchuan, China
Search for more papers by this authorSien Zhao
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorXu Cao
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorJinhai Tian
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorYuanyuan Yu
Department of Emergency, The General Hospital of Ningxia Medical University, Yinchuan, China
Search for more papers by this authorZhaoyang Fan
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorKun Xiao
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Search for more papers by this authorHui Zhao
Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Ministry of Education, The Chinese University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorCorresponding Author
Julhash U. Kazi
Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, Lund, Sweden
Correspondence Jianmin Sun
Email: [email protected]
Lijun Ma
Email: [email protected]
Julhash U. Kazi
Email: [email protected]
Search for more papers by this authorCorresponding Author
Lijun Ma
Department of Oncology, School of Medicine, Tongren Hospital, Shanghai Jiao Tong University, Shanghai, China
Correspondence Jianmin Sun
Email: [email protected]
Lijun Ma
Email: [email protected]
Julhash U. Kazi
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jianmin Sun
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Correspondence Jianmin Sun
Email: [email protected]
Lijun Ma
Email: [email protected]
Julhash U. Kazi
Email: [email protected]
Search for more papers by this authorAbstract
Gastrointestinal stromal tumors (GISTs) are predominantly initiated by KIT mutations. In this study, we observed that discoidin domain receptors 1 and 2 (DDR1 and DDR2) exhibited high expression in GISTs, were associated with KIT, and enhanced the activation of both wild-type KIT and primary KIT mutants. Inhibition of DDR1/2 led to a reduction in the activation of KIT and its downstream signaling molecules, ultimately impairing GIST cell survival and proliferation in vitro. Consequently, treatment of mice carrying germline KIT/V558A mutation with DDR1/2 inhibitor significantly impeded tumor growth, and the combined use of DDR1/2 inhibitor and imatinib, the first-line targeted therapeutic agent for GISTs, markedly enhanced tumor growth suppression. In addition, DDR1/2 inhibition resulted in decreased KIT expression, while KIT inhibition led to upregulation of DDR1/2 expression in GISTs. The presence of DDR1/2 also decreased the sensitivity of wild-type KIT or primary KIT mutants to imatinib, indicating a possible role for DDR1/2 in promoting GIST survival during KIT-targeted therapy. The development of drug-resistant secondary KIT mutations is a primary factor contributing to GIST recurrence following targeted therapy. Similar to primary KIT mutants, DDR1/2 can associate with and enhance the activation of secondary KIT mutants, further diminishing their sensitivity to imatinib. In summary, our data demonstrate that DDR1/2 contribute to KIT activation in GISTs and strengthen resistance to imatinib for both primary and secondary KIT mutants, providing a rationale for further exploration of DDR1/2 targeting in GIST treatment.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data support the findings in this study are available from the corresponding author upon reasonable request.
Supporting Information
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