title: Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells.
abstract: Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs.
  
  
  
  The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing. The responses of the AGCTs were compared with those of human granulosa luteal cells and bone marrow mononuclear cells.
  
  
  
  Patient-derived AGCT cells showed selective sensitivity to the Src family tyrosine kinase inhibitor dasatinib. A combination of either dasatinib or an mTOR-inhibitor everolimus with paclitaxel resulted in synergistic inhibition of AGCT cell viability. The key kinase targets of dasatinib and members of the mTOR pathway were constantly expressed at mRNA and protein levels, indicating multikinase signal addictions in the AGCT cells. Transcriptomic characterization of the tumors revealed no known oncogenic mutations, suggesting that the drug sensitivity of AGCTs was rather conveyed by selective target expression.
  
  
  
  We used a systematic functional approach to reveal novel treatment options for a unique gynecological cancer. The selective synergy found between taxanes and dasatinib or mTOR inhibitors warrants further clinical investigations of these combinations in relapsed or aggressive AGCTs and demonstrate that high-throughput drug screening and molecular profiling can provide an effective approach to uncover new therapy options.
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, PO Box 20, 00014 University of Helsinki, Finland; Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, PO Box 140, 00290 Helsinki, Finland.
authors.forename: Ulla-Maija
authors.initials: UM
authors.lastname: Haltia
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, PO Box 20, 00014 University of Helsinki, Finland.
authors.forename: Noora
authors.initials: N
authors.lastname: Andersson
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, 00014 Helsinki, Finland.
authors.forename: Bhagwan
authors.initials: B
authors.lastname: Yadav
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, PO Box 20, 00014 University of Helsinki, Finland; Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, PO Box 140, 00290 Helsinki, Finland. Electronic address: anniina.farkkila@helsinki.fi.
authors.forename: Anniina
authors.initials: A
authors.lastname: Färkkilä
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, 00014 Helsinki, Finland.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Kulesskiy
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, 00014 Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Kankainen
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, 00014 Helsinki, Finland.
authors.forename: Jing
authors.initials: J
authors.lastname: Tang
authors.affiliation: Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, PO Box 400, 00290 Helsinki, Finland.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.affiliation: Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, PO Box 140, 00290 Helsinki, Finland.
authors.forename: Annika
authors.initials: A
authors.lastname: Riska
authors.affiliation: Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, PO Box 140, 00290 Helsinki, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Leminen
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, PO Box 20, 00014 University of Helsinki, Finland; Department of Pediatrics, Washington University School of Medicine, St Louis Children's Hospital, St Louis, MO 63110, USA.
authors.forename: Markku
authors.initials: M
authors.lastname: Heikinheimo
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, 00014 Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.affiliation: Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, PO Box 140, 00290 Helsinki, Finland.
authors.forename: Leila
authors.initials: L
authors.lastname: Unkila-Kallio
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, 00014 Helsinki, Finland.
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, 00014 Helsinki, Finland; Department of Mathematics and Statistics, University of Turku, 20014 Turku, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Aittokallio
authors.affiliation: Clinical Chemistry and Hematology, University of Helsinki and HUSLAB, Helsinki University Hospital, PO Box 400, 00290 Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Anttonen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000008:administration & dosage / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006106:Granulosa Cell Tumor / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; D000069439:Dasatinib
keywords: Granulosa cell tumor; Kinase inhibitors; Ovarian cancer; Screening strategies