Abstract B162: Inhibition of the p110α isoform of PI 3-kinase prevents PIK3CA H1047R mutant tumor growth but is associated with impaired glucose metabolism.
Authors: Jamieson Stephen M. , Smith Greg C. , Kolekar Sharada , Lee Woo-Jeong , Singh Ripudaman , Buchanan Christina , Denny William A. , Han Weiping , Kendall Jackie D. , Rewcastle Gordon W. , Shepherd Peter R. 
Published: June 2012

Abstract
Signaling through the phosphoinositide 3-kinase (PI3K) pathway promotes cell survival and proliferation, but is also involved in the regulation of glucose metabolism. The PI3K pathway is frequently deregulated in cancer through amplification or mutational activation of the PIK3CA oncogene or deletion of the PTEN tumor suppressor gene. Therefore, PI3K has become a promising target for anticancer drug development, with several drugs that target multiple PI3K isoforms and mTOR (mammalian target of rapamycin) currently under clinical development. However, although class Ia PI3K oncogenic mutants have only been identified for the PIK3CA-encoded p110α isoform, there is a lack of drugs that have been developed to specifically target p110α and to identify the impact of p110α inhibition on tumor growth and glucose metabolism. In this study, we have investigated small molecule inhibitors of p110α that specifically target cells harboring the PIK3CA H1047R mutation. The selectivity of the inhibitors was confirmed by their potency against different PI3K isoforms and cellular activity was determined by their effect on pAkt expression. Tumor xenograft models with PIK3CA, PIK3CA/KRAS or PTEN mutations were used to evaluate the effect of p110α inhibition on tumor growth, while the role of p110α in glucose metabolism was investigated by tolerance to insulin, pyruvate and glucose in mice treated with PI3K inhibitors. Inhibition of p110α alone knocked down pAkt expression, with the greatest effect observed in cell lines that harbored the PIK3CA H1047R mutation and were wild-type for KRAS. A similar pattern emerged in human tumor xenograft models, where inhibition of p110 resulted in greater antitumor efficacy in SK-OV-3 (PIK3CA H1047R mutation) tumors than in HCT-116 (PIK3CA H1047R, KRAS G13D) or U87MG (PTEN deletion) tumors. In addition to delaying tumor growth, p110α inhibition also resulted in impaired glucose metabolism. The blood glucose or plasma insulin levels after administration of insulin, pyruvate or glucose were significantly elevated for up to 3 hrs in mice treated with p110α inhibitors relative to blood glucose or plasma insulin levels in control-treated mice. Similar effects on glucose metabolism were observed for pan-PI3K inhibitors, but not for selective inhibitors of other PI3K class Ia isoforms: p110α or p110α. These results suggest that selective targeting of the p110α isoform of PI3K is a viable anticancer therapeutic option, particularly for the subset of cancers harboring PIK3CA mutations. However, since p110α also appears to be necessary for regular glucose metabolism in vivo, treatment with p110α-selective PI3K inhibitors is likely to be adversely associated with hyperglycemia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B162.