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" mutations into breast epithelial cells identify new therapeutic targets associated with oncogenic PIK3CA. Mutant knockin were capable of epidermal growth factor and mTOR-independent cell proliferation that was AKT, ERK, GSK3beta phosphorylation. Paradoxically, the inhibitors lithium chloride SB216763 selectively decreased colorectal cancer lines led a decrease target CYCLIN D1. Oral treatment preferentially inhibited nude mouse xenografts HCT-116 colon mutant compared isogenic knockout containing only wild-type Our findings suggest an important effector PIK3CA, lithium, FDA-approved therapy for bipolar disorders, has selective antineoplastic properties against cancers harbor these mutations.