title: Activation of PI3K signaling in Merkel cell carcinoma.
abstract: OBJECTIVE
  Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor, often metastatic at presentation, for which current chemotherapeutic regimens are largely ineffective. As its pathogenesis is still unknown, we hypothesized that deregulation of signaling pathways commonly activated in cancer may contribute to MCC tumorigenesis and may provide insights into targeted therapy approaches for this malignancy.
  
  
  METHODS
  We retrospectively profiled 60 primary MCC samples using a SNaPshot-based tumor genotyping assay to screen for common mutations in 13 cancer genes.
  
  
  RESULTS
  We identified mutations in 9 (15%) MCC primary tumors, including mutations in TP53 (3 of 60) and activating mutations in the PIK3CA gene (6 of 60). Sanger sequencing of the primary MCC tumors detected one additional PIK3CA mutation (R19K) that had not been previously described in cancer. Merkel cell polyoma virus (MCPyV) was detected in 38 (66%) MCC cases and patients with MCPyV-positive cancers showed a trend toward better survival. With one exception, the presence of MCPyV and activating mutations in PIK3CA appeared mutually exclusive. We observed that signaling through the PI3K/pAKT pathway was active in one MCPyV-positive and in all MCPyV-negative MCC cell lines, as evidenced by AKT phosphorylation. Importantly, the presence of a PIK3CA-activating mutation was associated with sensitivity to treatment with ZST474, a specific phosphoinositide 3-kinase (PI3K) inhibitor, and to NVP-BEZ235, a dual PI3K/mTOR inhibitor, targeted agents under active clinical development.
  
  
  CONCLUSIONS
  PI3K pathway activation may drive tumorigenesis in a subset of MCC and screening these tumors for PIK3CA mutations could help identify patients who may respond to treatment with PI3K pathway inhibitors.
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02214, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Nardi
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Song
authors.forename: Juan A
authors.initials: JA
authors.lastname: Santamaria-Barria
authors.forename: Arjola K
authors.initials: AK
authors.lastname: Cosper
authors.forename: Quynh
authors.initials: Q
authors.lastname: Lam
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.forename: Genevieve M
authors.initials: GM
authors.lastname: Boland
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.forename: Kristin
authors.initials: K
authors.lastname: Bergethon
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Scialabba
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.forename: Atul K
authors.initials: AK
authors.lastname: Bhan
authors.forename: Mai P
authors.initials: MP
authors.lastname: Hoang
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: James C
authors.initials: JC
authors.lastname: Cusack
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D015266:Carcinoma, Merkel Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C484760:PIK3CA protein, human