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DDR1/2 enhance KIT ...
DDR1/2 enhance KIT activation and imatinib resistance of primary and secondary KIT mutants in gastrointestinal stromal tumors
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- Liu, Anbu (author)
- Ningxia Medical University
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- Zhang, Shaoting (author)
- Ningxia Medical University
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- Wang, Ming (author)
- Ningxia Medical University
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- Zhang, Liangying (author)
- Ningxia Medical University
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- Xu, Shidong (author)
- Tongren Hospital Shanghai Jiao Tong University School Of Medicine
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- Nasimian, Ahmad (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Li, Shujing (author)
- Ningxia Medical University
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- Zhao, Sien (author)
- Ningxia Medical University
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- Cao, Xu (author)
- Ningxia Medical University
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- Tian, Jinhai (author)
- Ningxia Medical University
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- Yu, Yuanyuan (author)
- Ningxia Medical University
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- Fan, Zhaoyang (author)
- Ningxia Medical University
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- Xiao, Kun (author)
- Ningxia Medical University
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- Zhao, Hui (author)
- Chinese University of Hong Kong
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- Kazi, Julhash U. (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Ma, Lijun (author)
- Tongren Hospital Shanghai Jiao Tong University School Of Medicine
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- Sun, Jianmin (author)
- Ningxia Medical University
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(creator_code:org_t)
- 2024
- 2024
- English 19 s.
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In: Molecular Carcinogenesis. - 0899-1987. ; 63:1, s. 75-93
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- DDR
- GIST
- imatinib
- KIT
- mutation
Publication and Content Type
- art (subject category)
- ref (subject category)
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To the university's database
- By the author/editor
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Liu, Anbu
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Zhang, Shaoting
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Wang, Ming
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Zhang, Liangying
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Xu, Shidong
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Nasimian, Ahmad
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show more...
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Li, Shujing
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Zhao, Sien
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Cao, Xu
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Tian, Jinhai
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Yu, Yuanyuan
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Fan, Zhaoyang
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Xiao, Kun
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Zhao, Hui
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Kazi, Julhash U.
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Ma, Lijun
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Sun, Jianmin
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Molecular Carcin ...
- By the university
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Lund University