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.

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