Knockin of mutant PIK3CA activates multiple oncogenic pathways

• DOI: 10.1073/pnas.0813351106
• Publication Date: 2009-02-07T05:06:11Z
• Authors: John P. Gustin; Bedri Karakas; Michele B. Weiss; Abde M. Abukhdeir; Josh Lauring; Joseph P. Garay; David Cosgrove; Akina Tamaki; Hiroyuki Konishi; Yuko Konishi; Morassa Mohseni; Grace Wang; D. Marc Rosen; Samuel R. Denmeade; Michaela J. Higgins; Michele I. Vitolo; Kurtis E. Bachman; Ben Ho Park
• Keywords: 0301 basic medicine; 0303 health sciences; Glycogen Synthase Kinase 3 beta; Class I Phosphatidylinositol 3-Kinases; TOR Serine-Threonine Kinases; Mice, Nude; Breast Neoplasms; Oncogenes; 3. Good health; Glycogen Synthase Kinase 3; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Cell Line, Tumor; Mutation; Animals; Humans; Gene Knock-In Techniques; Phosphorylation; Colorectal Neoplasms; Extracellular Signal-Regulated MAP Kinases; Mammary Glands, Human; Protein Kinases; Proto-Oncogene Proteins c-akt

The phosphatidylinositol 3-kinase subunit PIK3CA is frequently mutated in human cancers. Here we used gene targeting to “knock in” PIK3CA mutations into human breast epithelial cells to identify new therapeutic targets associated with oncogenic PIK3CA. Mutant PIK3CA knockin cells were capable of epidermal growth factor and mTOR-independent cell proliferation that was associated with AKT, ERK, and GSK3β phosphorylation. Paradoxically, the GSK3β inhibitors lithium chloride and SB216763 selectively decreased the proliferation of human breast and colorectal cancer cell lines with oncogenic PIK3CA mutations and led to a decrease in the GSK3β target gene CYCLIN D1 . Oral treatment with lithium preferentially inhibited the growth of nude mouse xenografts of HCT-116 colon cancer cells with mutant PIK3CA compared with isogenic HCT-116 knockout cells containing only wild-type PIK3CA . Our findings suggest GSK3β is an important effector of mutant PIK3CA , and that lithium, an FDA-approved therapy for bipolar disorders, has selective antineoplastic properties against cancers that harbor these mutations.