title: Perifosine, an AKT inhibitor, modulates ovarian cancer cell line sensitivity to cisplatin-induced growth arrest.
abstract: OBJECTIVE
  AKT, a key regulator of diverse tumor signaling, is associated with progression of many cancers. Here, we investigated 1) the influence of AKT on survival from ovarian cancer (OVCA), 2) the activity of the AKT inhibitor perifosine ± cisplatin, and 3) the molecular determinants of perifosine-response. Phospho-AKT expression values and Affymetrix U133a expression data were downloaded from The Cancer Genome Atlas.
  
  
  METHODS
  Pearson correlation was used to determine associations between overall survival from OVCA and therapy response. Genes and represented signaling pathways associated with perifosine-response were explored in OVCA cells (n=10) and the NCI60 cancer cell panel. Pathway expressions, modeled by PCA, were evaluated for influences on survival using publically available clinico-genomic datasets.
  
  
  RESULTS
  Phospho-AKT (serine473) expression correlated with survival from OVCA (P<0.05) and platinum-response (P=0.004). In vitro, perifosine showed anti-proliferative effects against OVCA cells and potentiated cisplatin-induced growth arrest. Perifosine-response was associated with the expression (FDR<0.05) of 7 signaling pathways in OVCA cells and 64 signaling pathways in the NCI60 cell panel. Three pathways were found in common: 1) Cytoskeleton remodeling/cytoskeleton remodeling (cyto), 2) cell adhesion/chemokines and adhesion (chemokines), and 3) cytoskeleton remodeling/TGF-WNT (TGF-WNT). The TGF-WNT was associated with survival from OVCA (P=0.0055).
  
  
  CONCLUSIONS
  AKT signaling is an important determinant of OVCA response to chemotherapy and overall patient survival. Our data provide insight into the molecular basis to perifosine activity and identifies pathways associated with perifosine sensitivity and patient clinical outcome.
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Entidhar
authors.initials: E
authors.lastname: Al Sawah
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Marchion
authors.forename: Yin
authors.initials: Y
authors.lastname: Xiong
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Ramirez
authors.forename: Forough
authors.initials: F
authors.lastname: Abbasi
authors.forename: Nadim
authors.initials: N
authors.lastname: Bou Zgheib
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Chon
authors.forename: Robert M
authors.initials: RM
authors.lastname: Wenham
authors.forename: Sachin M
authors.initials: SM
authors.lastname: Apte
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Judson
authors.forename: Johnathan M
authors.initials: JM
authors.lastname: Lancaster
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012313:RNA / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D010767:Phosphorylcholine; C105905:perifosine; D012313:RNA; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin
keywords: AKT; Cisplatin; Gene expression; Ovarian CANCER; Perifosine