PI3 Kinase in Cancer: From Biology to Clinic

Overview: The discovery and clinical development of small-molecule inhibitors of the phosphatidylinositide 3-kinase (PI3 kinase) family of lipid kinases have marked a remarkable 20-year journey that follows the progressive developments in cancer biology over the last few decades: from hypothesis-driven, basic cancer research that began with viral oncogenesis and developed in the 1960s and 70s, through the discovery of individual mutated oncogenes and tumor suppressor genes in 1970 and 80s and the linkage of these cancer genes to signal transduction pathways in the 1990s, to all large-scale genome-wide sequencing, functional screening, and network biology efforts today. Thus, PI3 kinase research began with the discovery in 1985 of a new type of enzyme activity associated with viral oncogenesis. It benefited greatly from the discovery of wortmannin and LY294002 as PI3 kinase inhibitors and chemical tools in late 1980s to mid-90s. Alongside these tools, genetic validation of PI3 kinase as a target initially involved activation by upstream oncogenic receptor tyrosine kinases and RAS mutation, together with overexpression and amplification of the p110α catalytic isoform of PI3 kinase and frequent loss of the tumor suppressor and negative regulator of PI3 kinase activity, PTEN. As PI3 kinase drug development began, further stimulus came from the discovery through genome sequencing of mutations in PIK3CA, which encodes p110α and is the most frequently mutated kinase in the human genome. From these beginnings, there are now many PI3 kinase inhibitors in clinical trials and more in preclinical development. We review progress, current challenges, and future opportunities in this article.