Abstract SY34-01: Biomarkers for predicting response to PI3K inhibitors

Abstract

Abstract Phosphoinositide 3-kinase (PI 3-kinase) is a central enzyme in a signaling pathway that mediates cellular responses to growth factors. The pathway is highly conserved from worms and flies to humans and genetic analysis of the pathway has revealed a conserved role in regulating glucose metabolism, cell growth and organism longevity. Based on deletion of genes encoding the catalytic or regulatory subunits of PI 3-kinase in the mouse, PI 3-kinase mediates insulin-dependent regulation of glucose metabolism, and defects in activation of this pathway result in insulin resistance and type 2 diabetes. In contrast, mutational events that lead to hyperactivation of PI 3-kinase result in cancers. Activating mutations in PIK3CA, encoding the p110alpha catalytic subunit of PI 3-kinase or inactivating mutations in PTEN, a phosphoinositide 3-phosphatases that reverses the effects of PI 3-kinase, are among the most common events in solid tumors. We, and others have generated mouse models in which a mutated form of the PIK3CA gene is expressed in a tissue-specific and reversibly inducible manner. These mice develop cancers that are dependent on continuous expression of the mutant PIK3CA gene. The PIK3CA driven tumors are FDG-PET positive and turning off PI 3-kinase with drugs results in an acute decline in FDG-PET signal that precedes tumor shrinkage. These results suggest that the ability of PI 3-kinase to stimulate high rates of glucose uptake and metabolism may be critical for the survival of PIK3CA mutant tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY34-01. doi:10.1158/1538-7445.AM2011-SY34-01