title: Genomic complexity and AKT dependence in serous ovarian cancer.
abstract: 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.
  
  
  CONCLUSIONS
  A subset of ovarian cancers exhibits AKT pathway activation and is sensitive to selective AKT inhibition. Ovarian tumors exhibit significant genetic heterogeneity and thus an individualized approach based on real-time, detailed genomic and proteomic characterization of individual tumors will be required for the successful application of PI3K/AKT pathway inhibitors in this disease.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10471, USA.
authors.forename: Aphrothiti J
authors.initials: AJ
authors.lastname: Hanrahan
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Maggie L
authors.initials: ML
authors.lastname: Westfal
authors.forename: Rita A
authors.initials: RA
authors.lastname: Sakr
authors.forename: Dilip D
authors.initials: DD
authors.lastname: Giri
authors.forename: Stefano
authors.initials: S
authors.lastname: Scarperi
authors.forename: Manickam
authors.initials: M
authors.lastname: Janakiraman
authors.forename: Manickam
authors.initials: M
authors.lastname: Janikariman
authors.forename: Narciso
authors.initials: N
authors.lastname: Olvera
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Stevens
authors.forename: Qing-Bai
authors.initials: QB
authors.lastname: She
authors.forename: Carol
authors.initials: C
authors.lastname: Aghajanian
authors.forename: Tari A
authors.initials: TA
authors.lastname: King
authors.forename: Elisa de
authors.initials: Ed
authors.lastname: Stanchina
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
mesh_terms: D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D023281:Genomics; D006801:Humans; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D051057:Proto-Oncogene Proteins c-akt