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Knockin of mutant PIK3CA activates multiple oncogenic pathways
John P Gustin1, Bedri Karakas, Michele B Weiss
1The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Summary
Oncogenic PIK3CA mutations drive cancer cell proliferation. GSK3beta inhibition, using lithium, selectively reduces cancer growth, suggesting lithium as a potential cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The phosphatidylinositol 3-kinase subunit PIK3CA is frequently mutated in various human cancers.
- Oncogenic PIK3CA mutations are linked to uncontrolled cell proliferation and tumor growth.
Purpose of the Study:
- To identify novel therapeutic targets associated with oncogenic PIK3CA.
- To investigate the role of GSK3beta in mediating the effects of mutant PIK3CA.
Main Methods:
- Gene targeting to introduce PIK3CA mutations into human breast epithelial cells.
- Assessment of cell proliferation, phosphorylation of signaling proteins (AKT, ERK, GSK3beta), and target gene expression (CYCLIN D1).
- Evaluation of lithium's efficacy in inhibiting cancer cell line and xenograft growth in vivo.
Main Results:
- Mutant PIK3CA knockin cells exhibited epidermal growth factor and mTOR-independent proliferation.
- GSK3beta inhibitors (lithium chloride, SB216763) selectively reduced proliferation of cancer cell lines with PIK3CA mutations.
- Lithium treatment preferentially inhibited the growth of PIK3CA-mutant colon cancer xenografts in mice.
- Inhibition of GSK3beta led to decreased expression of its target gene, CYCLIN D1.
Conclusions:
- GSK3beta is a critical effector of oncogenic PIK3CA.
- Lithium chloride demonstrates selective antineoplastic properties against cancers harboring PIK3CA mutations.
- FDA-approved lithium may serve as a potential therapeutic agent for PIK3CA-mutant cancers.
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