title: Activation of the PI3K/AKT pathway in Merkel cell carcinoma.
abstract: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.
authors.affiliation: Department of Dermatology, University of Regensburg, Regensburg, Germany. christian.hafner@klinik.uni-regensburg.de
authors.forename: Christian
authors.initials: C
authors.lastname: Hafner
authors.forename: Roland
authors.initials: R
authors.lastname: Houben
authors.forename: Anne
authors.initials: A
authors.lastname: Baeurle
authors.forename: Cathrin
authors.initials: C
authors.lastname: Ritter
authors.forename: David
authors.initials: D
authors.lastname: Schrama
authors.forename: Michael
authors.initials: M
authors.lastname: Landthaler
authors.forename: Juergen C
authors.initials: JC
authors.lastname: Becker
mesh_terms: D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D001483:Base Sequence; D002280:Basal Cell Carcinoma / Q000201:enzymology / Q000473:pathology; D015266:Carcinoma, Merkel Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D000952:Antigens, Polyomavirus Transforming; D002867:Chromones; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010769:Phosphothreonine; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one