The PIK3CA gene as a mutated target for cancer therapy.
The development of targeted therapies with true specificity for cancer relies upon exploiting differences between cancerous and normal cells. Genetic and genomic alterations including somatic mutations, translocations, and amplifications have served as recent examples of how such differences can be exploited as effective drug targets. Small molecule inhibitors and monoclonal antibodies directed against the protein products of these genetic anomalies have led to cancer therapies with high specificity and relatively low toxicity. Recently, our group and others have demonstrated that somatic mutations in the PIK3CA gene occur at high frequency in breast and other cancers. Moreover, the majority of mutations occur at three hotspots, making these ideal targets for therapeutic development. Here we review the literature on PIK3CA mutations in cancer, as well as existing data on PIK3CA inhibitors and inhibitors of downstream effectors for potential use as targeted cancer therapeutics.
Gustin
John P
JP
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21231, USA.
Cosgrove
David P
DP
Park
Ben Ho
BH
D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D058570:TOR Serine-Threonine Kinases
D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human