Genomic complexity and AKT-dependence in serous ovarian cancer
Menée sur des lignées cellulaires et des tumeurs de cancer ovarien, cette étude identifie des altérations de gènes impliqués dans la voie de signalisation PI3K/AKT et analyse leurs conséquences sur la sensibilité des cellules tumorales à des inhibiteurs de AKT
Effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer. To explore the role of PI3 kinase/AKT signaling in this disease, we performed a genetic and functional analysis of ovarian cancer cell lines and tumors. PI3k pathway alterations were common in both, but the spectrum of mutational changes differed. Genetic activation of the pathway was necessary, but not sufficient, to confer sensitivity to selective inhibition of AKT and cells with RAS-pathway alterations or RB1-loss were resistant to AKT inhibition, whether or not they had coexistent PI3k/AKT pathway activation. Inhibition of AKT1 caused growth arrest in a subset of ovarian cell lines, but not in those with AKT3 expression, which required pan-AKT inhibition. Thus, a subset of ovarian tumors are sensitive to AKT inhibition, but the genetic heterogeneity of the disease suggests that effective treatment with AKT pathway inhibitors will require a detailed molecular analysis of each patient's tumor.
Cancer Discovery 2011