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Three decades of basic cancer research have revealed that mutations in components of signalling pathways that control cell growth in primitive metazoans underlie tumour initiation in mammals. The Ras, PI(3)K and mTOR (mammalian target of rapamycin) signalling pathways form an intersecting biochemical network that, when mutated, drives cell growth in a manner unrestricted by environmental cues. Ultimately, these pathways drive tumorigenesis through the coordinated phosphorylation of proteins that directly regulate protein synthesis, cell-cycle progression and metabolism, and of transcription factors that regulate the expression of genes involved in these processes. The basic elements of this biochemical network are outlined in Fig. 1. Growth factors activate receptor tyrosine kinases (RTKs), which then activate two key signal-transduction components: the small GTPase Ras and the lipid kinase PI(3)K. Most human tumours harbour activating mutations in these master regulators (K-ras, H-ras, N-ras, the p110α PI(3)K subunit and RTKs), or inactivating mutations in negative regulators of these proteins (phosphatase and tensin homologue (PTEN) and neurofibromin 1 (NF1)). More recent genomic sequencing efforts have also revealed oncogenic mutations in several downstream components of these pathways. The serine/threonine kinase mTOR is a highly conserved integrator of both mitogenic and nutrient inputs in yeast and mammalian cells, and has been shown to control cell growth in response to various environ mental cues. Recent discoveries indicate that the Ras and PI(3)K pathways converge to activate mTOR to stimulate cell growth. Notably, several tumour suppressors of previously unknown function (tuberous sclerosis complex 1 (TSC1, also known as hamartin), TSC2 (tuberin) and serine/threonine protein kinase 11 (LKB1)) have recently been shown to attenuate mTOR signalling under nutrient-poor conditions. Accordingly, inactivation of TSC1, TSC2 or LKB1, or of the aforementioned PTEN and NF1, results in familial cancer syndromes with shared clinical features (phakomatoses). So, this ancestral network, which evolved to ensure that cell proliferation occurs only under environmentally favourable conditions, has been exploited by cancer cells to promote growth and survival under inappropriate conditions. Recent pharmaceutical efforts in developing kinase inhibitors have resulted in a number of agents designed to inhibit the kinase components of these signalling pathways (mTOR, PI(3)K, RTKs, Raf and AKT). Ras, PI(3)K and mTOR signalling controls tumour cell growth