Insulin–PI3K signalling: an evolutionarily insulated metabolic driver of cancer

Cancer is driven by incremental changes that accumulate, eventually leading to oncogenic transformation. Although genetic alterations dominate the way cancer biologists think about oncogenesis, growing evidence suggests that systemic factors (for example, insulin, oestrogen and inflammatory cytokines) and their intracellular pathways activate oncogenic signals and contribute to targetable phenotypes. Systemic factors can have a critical role in both tumour initiation and therapeutic responses as increasingly targeted and personalized therapeutic regimens are used to treat patients with cancer. The endocrine system controls cell growth and metabolism by providing extracellular cues that integrate systemic nutrient status with cellular activities such as proliferation and survival via the production of metabolites and hormones such as insulin. When insulin binds to its receptor, it initiates a sequence of phosphorylation events that lead to activation of the catalytic activity of phosphoinositide 3-kinase (PI3K), a lipid kinase that coordinates the intake and utilization of glucose, and mTOR, a kinase downstream of PI3K that stimulates transcription and translation. When chronically activated, the PI3K pathway can drive malignant transformation. Here, we discuss the insulin–PI3K signalling cascade and emphasize its roles in normal cells (including coordinating cell metabolism and growth), highlighting the features of this network that make it ideal for co-option by cancer cells. Furthermore, we discuss how this signalling network can affect therapeutic responses and how novel metabolic-based strategies might enhance treatment efficacy for cancer. This Review discusses the connections between insulin signalling and oncogenic transformation, highlighting the potential effect of insulin as a pro-tumorigenic factor. The latest studies examining new approaches to circumvent systemic insulin feedback to increase the antitumour effect of agents targeting the insulin signalling pathway are discussed. Key points Systemic factors such as insulin activate the same signalling pathways as some of the most recurrent mutations in human cancer. The phosphoinositide 3-kinase (PI3K) signalling cascade, which is activated by insulin, regulates cellular metabolism and cell fate decisions, including cell survival and proliferation. High insulin levels can promote and sustain tumour growth. Therapeutic targeting of the PI3K signalling cascade is subject to a variety of cellular a