Abstract

Phosphoinositide 3-kinase (PI3K) is a central enzyme in a signalling pathway that mediates cellular responses to insulin and other growth factors. The signalling pathway involving insulin, PI3K and the downstream components of AKT and mTOR is highly conserved from worms and flies to humans and genetic analysis of the pathway has revealed a conserved role in regulating glucose metabolism and cell growth. Germline mutational events that lead to hyperactivation of the PI3K pathway result in hamartoma syndromes and cancers. Sporadic activating mutations in PIK3CA, encoding the p110alpha catalytic subunit of PI3K or inactivating mutations in PTEN (a phosphoinositide 3-phosphatase that reverses the effects of PI3K) are among the most common events in solid tumours. More than thirty drugs that target PI3K and other components of this pathway are in clinical trials for a variety of cancers. It is likely that PI3K pathway inhibitors will need to be combined with other drugs to be broadly effective. We have employed genetically engineered mouse models that develop cancers due to mutations in genes in the PI3K pathway and are using these models to explore the efficacy of PI3K pathway inhibitors as single agents or in combination with other drugs. The role of PI3K inhibitors for treating cancers in these mouse models and in human trials will be discussed.