Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis

Abstract

The phosphatidylinositol 3-kinase (PI3K)–phosphatase with tensin homology (PTEN) signalling pathway is one of the most commonly altered pathways in human tumours. However, mutations of the PTEN gene itself account for only a fraction of these molecular changes. The PI3K–PTEN pathway promotes cell survival and proliferation, increases in cell size and chemoresistance. Each of these biological outcomes results from the interaction of this pathway with other signalling networks. Ras and its downstream effectors can activate components of the PI3K–PTEN pathway through numerous mechanisms. Each mechanism might be restricted to a particular tumour type, allowing the design of a specific therapy that kills cancer cells but leaves normal tissue unharmed. Crosstalk between the PI3K–PTEN and p53 pathways occurs at multiple nodes in these pathways. When both PTEN and p53 are inactivated by mutations, malignancy is promoted in a synergistic manner. The Ras, PI3K–PTEN and p53 pathways all converge either directly or indirectly on the tumour suppressor TSC2, indicating a crucial role for this molecule in the integration of multiple signals. DJ1 is a novel regulator of the PI3K–PTEN pathway and is associated with breast and lung cancers. The multiple pathways that influence the PI3K–PTEN signalling network do so through a variety of mechanisms, providing numerous potential drug targets. Drugs that act on these targets could be formulated to work either synergistically with agents that act directly on PI3K or on elements that function downstream of mutated pathway components. These drugs might offer an attractive additional or alternative approach to combating PI3K-dependent tumours.