title: KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer.
abstract: The discovery of mutant KRAS as a predictor of resistance to epidermal growth-factor receptor (EGFR) monoclonal antibodies brought a major change in the treatment of metastatic colorectal cancer. This seminal finding also highlighted our sparse knowledge about key signalling pathways in colorectal tumours. Drugs that inhibit oncogenic alterations such as phospho-MAP2K (also called MEK), phospho-AKT, and mutant B-RAF seem promising as single treatment or when given with EGFR inhibitors. However, our understanding of the precise role these potential drug targets have in colorectal tumours, and the oncogenic dependence that tumours might have on these components, has not progressed at the same rate. As a result, patient selection and prediction of treatment effects remain problematic. We review the role of mutations in genes other than KRAS on the efficacy of anti-EGFR therapy, and discuss strategies to target these oncogenic alterations alone or in combination with receptor tyrosine-kinase inhibition.
authors.affiliation: Centre for Human Genetics, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Wendy
authors.initials: W
authors.lastname: De  Roock
authors.forename: Veerle
authors.initials: V
authors.lastname: De Vriendt
authors.forename: Nicola
authors.initials: N
authors.lastname: Normanno
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
mesh_terms: D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D009154:Mutation; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D018631:ras Proteins / Q000235:genetics*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D048369:MAP Kinase Kinase 1; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C482119:BRAF protein, human; C494929:PTEN protein, human