- 作者：Entidhar Al Sawah ; Xin Chen ; Douglas C. Marchion ; Yin Xiong ; Ingrid J. Ramirez ; Forough Abbasi ; Nadim Bou Zgheib ; Hye Sook Chon ; Robert M. Wenham ; Sachin M. Apte ; Patricia L. Judson ; Johnathan M. Lancaster
- 关键词：Perifosine ; Cisplatin ; AKT ; Ovarian CANCER ; Gene expression
- 刊名：Gynecologic Oncology
- 出版年：2013
- 出版时间：October, 2013
- 年：2013
- 卷：131
- 期：1
- 页码：207-212
- 全文大小：399 K
Objectives
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 ¡À 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.