title: Targeting Src in endometriosis-associated ovarian cancer.
abstract: The SRC proto-oncogene is commonly overexpressed or activated during cancer development. Src family kinase inhibitors are approved for the treatment of certain leukemias, and are in clinical trials for the treatment of solid tumors. Src signaling is activated in endometriosis, a precursor of clear cell and endometrioid subtypes of epithelial ovarian cancers (OCs). We examined the expression of phosphorylated Src (Src-pY416) in 381 primary OC tissues. Thirty-six percent of OCs expressed Src-pY416. Src-pY416 expression was most common in endometriosis-associated OCs (EAOCs) (P=0.011), particularly in clear cell OCs where 58.5% of cases expressed Src-pY416. Src-pY416 expression was associated with shorter overall survival (log rank P=0.002). In vitro inhibition of Src signaling using 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2) resulted in reduced anchorage-independent and -dependent growth, and in three-dimensional cell culture models PP2 disrupted aggregate formation in Src-pY416-positive but not in Src-pY416-negative cell lines. These data suggest that targeting active Src signaling could be a novel therapeutic opportunity for EAOCs, and support the further pre-clinical investigation of Src family kinase inhibitors for treating OCs expressing Src-pY416.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Manek
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Pakzamir
authors.affiliation: Departments of Medicine and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Mhawech-Fauceglia
authors.affiliation: Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: T
authors.initials: T
authors.lastname: Pejovic
authors.affiliation: Department of Biomedical Science and Public Health, University of Derby, Derby, UK.
authors.forename: H
authors.initials: H
authors.lastname: Sowter
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Gayther
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lawrenson