Cell-permeable PI3 kinase competitive peptide inhibits KIT mutant mediated tumorigenesis of gastrointestinal stromal tumor (GIST)
Related Experiment Video
Updated: Jul 5, 2025
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Zongying Jiang1, Yue Guo2, Jun Shi3
1NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
Background:
Mutations in the receptor tyrosine kinase KIT are the main cause of gastrointestinal stromal tumor (GIST), and the KIT mutants mediated PI3 kinase activation plays a key role in the tumorigenesis of GIST. In this study, we aimed to block PI3 kinase activation by cell-permeable peptide and investigate its possible application in the treatment of GIST.
Methods And Results:
We designed cell-permeable peptides based on the binding domain of PI3 kinase subunit p85 to KIT or PI3 kinase subunit p110, respectively, in order to compete for the binding between p85 and KIT or p110 and therefore inhibit the activation of PI3 kinases mediated by KIT. The results showed that the peptide can penetrate the cells, and inhibit the activation of PI3 kinases, leading to reduced cell survival and cell proliferation mediated by KIT mutants in vitro. Treatment of mice carrying germline KIT/V558A mutation, which can develop GIST, with the peptide that can compete for the binding between p85 and p110, led to reduced tumorigenesis of GIST. The peptide can further enhance the inhibition of the tumor growth by imatinib which is used as the first line targeted therapy of GIST.
Conclusions:
Our results showed that cell-permeable PI3 kinase competitive peptide can inhibit KIT-mediated PI3 kinase activation and tumorigenesis of GIST, providing a rationale to further test the peptide in the treatment of GIST and even other tumors with over-activation of PI3 kinases.
Insights
A novel peptide therapy targeting PI3 kinase activation shows promise for treating gastrointestinal stromal tumors (GIST). This peptide inhibits tumor growth and enhances imatinib efficacy, offering a new therapeutic avenue for GIST and other PI3K-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Mutations in the receptor tyrosine kinase KIT drive gastrointestinal stromal tumor (GIST) development.
- KIT-mediated PI3 kinase activation is crucial for GIST tumorigenesis.
Purpose of the Study:
- To develop a cell-permeable peptide to inhibit PI3 kinase activation.
- To investigate the peptide's therapeutic potential in GIST treatment.
Main Methods:
- Designed cell-permeable peptides targeting PI3 kinase subunits (p85 and p110) to disrupt KIT binding.
- Assessed peptide efficacy in vitro for cell survival and proliferation.
- Evaluated peptide treatment in mice with KIT/V558A mutation-induced GIST.
Main Results:
- Peptides successfully penetrated cells and inhibited PI3 kinase activation.
- In vitro studies showed reduced cell survival and proliferation.
- Peptide treatment reduced GIST tumorigenesis in mice.
- The peptide enhanced the anti-tumor effect of imatinib.
Conclusions:
- Cell-permeable PI3 kinase competitive peptides inhibit KIT-mediated activation and GIST tumorigenesis.
- This peptide strategy provides a rationale for GIST treatment.
- Potential application in other PI3K-overactive tumors.
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