Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells

Ulla-Maija Haltia; Noora Andersson; Bhagwan Yadav; Anniina Färkkilä; Evgeny Kulesskiy; Matti Kankainen; Jing Tang; Ralf Bützow; Annika Riska; Arto Leminen; Markku Heikinheimo; Olli Kallioniemi; Leila Unkila-Kallio; Krister Wennerberg; Tero Aittokallio; Mikko Anttonen

doi:10.1016/j.ygyno.2016.12.016

Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells

Gynecol Oncol. 2017 Mar;144(3):621-630. doi: 10.1016/j.ygyno.2016.12.016. Epub 2017 Jan 16.

Authors

Ulla-Maija Haltia¹, Noora Andersson², Bhagwan Yadav³, Anniina Färkkilä⁴, Evgeny Kulesskiy³, Matti Kankainen³, Jing Tang³, Ralf Bützow⁵, Annika Riska⁶, Arto Leminen⁶, Markku Heikinheimo⁷, Olli Kallioniemi³, Leila Unkila-Kallio⁶, Krister Wennerberg³, Tero Aittokallio⁸, Mikko Anttonen⁹

Affiliations

¹ 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.
² Children's Hospital, University of Helsinki and Helsinki University Hospital, PO Box 20, 00014 University of Helsinki, Finland.
³ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, 00014 Helsinki, Finland.
⁴ 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.
⁵ Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, PO Box 400, 00290 Helsinki, Finland.
⁶ Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, PO Box 140, 00290 Helsinki, Finland.
⁷ 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.
⁸ 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.
⁹ Clinical Chemistry and Hematology, University of Helsinki and HUSLAB, Helsinki University Hospital, PO Box 400, 00290 Helsinki, Finland.

PMID: 28104295
DOI: 10.1016/j.ygyno.2016.12.016

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Granulosa cell tumor; Kinase inhibitors; Ovarian cancer; Screening strategies.

MeSH terms

Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Cell Line, Tumor
Dasatinib / administration & dosage
Dasatinib / pharmacology*
Drug Screening Assays, Antitumor
Drug Synergism
Female
Granulosa Cell Tumor / drug therapy*
Granulosa Cell Tumor / pathology
Humans
Middle Aged
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / pathology
Paclitaxel / administration & dosage
Paclitaxel / pharmacology*
TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

MTOR protein, human
TOR Serine-Threonine Kinases
Paclitaxel
Dasatinib

Supplementary concepts

Granulosa cell tumor of the ovary