title: PTTG1 Levels Are Predictive of Saracatinib Sensitivity in Ovarian Cancer Cell Lines.
abstract: Src kinase is recognized as a key target for molecular cancer therapy. However, methods to efficiently select patients responsive to Src inhibitors are lacking. We explored the sensitivity of ovarian cancer cell lines to the Src kinase inhibitor saracatinib to identify predictive markers of drug sensitivity using gene microarrays. Pituitary tumor transforming gene 1 (PTTG1) was selected as a potential biomarker as mRNA levels were correlated with saracatinib resistance, as well as higher PTTG1 protein expression. PTTG1 expression was correlated with proliferation, cell division, and mitosis in ovarian cancer tissues data sets. In sensitive cell lines, saracatinib treatment decreased PTTG1 and fibroblast growth factor 2 (FGF2) protein levels. Downregulating PTTG1 by siRNAs increased saracatinib sensitivity in two resistant cell lines. Our results indicate PTTG1 may be a valuable biomarker in ovarian cancer to predict sensitivity to saracatinib, and could form the basis of a targeted prospective saracatinib trial for ovarian cancer.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver/Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: I
authors.initials: I
authors.lastname: Nakachi
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Denver/Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Helfrich
authors.affiliation: Department of Obstetrics and Gynecology, University of Colorado Denver/Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Spillman
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Mickler
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Olson
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver/Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Rice
authors.affiliation: PathGroup, Nashville, Tennessee, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Coldren
authors.affiliation: Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Denver/Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Heasley
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver/Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Geraci
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver/Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Stearman
mesh_terms: D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D064249:Securin / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D052117:Benzodioxoles; D011799:Quinazolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; D016222:Fibroblast Growth Factor 2; C515233:saracatinib; D019061:src-Family Kinases