Abstract C55: Efficacy of PI3K inhibitors to cancer cells with PIK3CA mutation or loss of PTEN expression

Abstract

Abstract Phosphoinositide 3-kinase (PI3K) pathway is frequently activated in cancer and is thought to be a promising therapeutic target. We previously reported a specific PI3K inhibitor ZSTK474 having a potent antitumor activity in vitro and in vivo without severe toxicity. Since then, diverse PI3K inhibitors have been developed, and some of them already entered clinical trials. Gain-of-function mutations of PIK3CA and loss of PTEN expression are frequently observed in various cancers and believed to activate PI3K-downstream effectors, but it is not well understood whether PI3K inhibitors have therapeutic efficacies against such cancers. In this study, taking advantage of pharmacologically well-characterized 39 human cancer cell lines (JFCR39), we examined the efficacies of eleven PI3K inhibitors including ZSTK474 and NVP-BEZ235, the mutational status and the protein expression levels of PIK3CA (p110) and PTEN in each of the cell lines. As a result, we found eight cell lines carrying missense mutations in PIK3CA. Most mutations were located in hotspot (E545K and H1047R), but some of them were in other residues. We evaluated kinase activities of these mutants and found that four of them including P449T (2.3-fold), E545K (8.5-fold), E545K/D549N (6.3-fold) and H1047R (5.8-fold) exhibited enhanced kinase activities compared to wild-type p110 , and seven of 39 cell lines had such mutation. On the other hand, mutational analysis of PTEN revealed that nine cell lines had missense mutation or deletion in PTEN, and seven of them did not express PTEN protein. Then, we compared the efficacies of PI3K inhibitors in cell lines with gain-of-function mutation of PIK3CA or loss of PTEN expression with those in other cell lines, and no significant correlation was observed. We further examined the inhibitory effect of three PI3K inhibitors on the enzymatic activity of p110 mutants, and all of three inhibited the kinase activity of E545K and H1047R mutant as well as wild-type p110 . These results suggested that PI3K inhibitors examined in this study were effective to cancer cells with PIK3CA mutation or PTEN loss equivalent to those having normal PIK3CA and PTEN expression, and that these PI3K inhibitors are applicable in clinical use for treatment of such cancers. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C55.