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Tyrosine Kinase Inhibitors as Potential Therapeutic Agents in the Treatment of Granulosa Cell Tumors of the Ovary
  1. Stacey Jamieson, PhD and
  2. Peter J. Fuller, BMedSci, MBBS, PhD, FRACP
  1. Prince Henry’s Institute of Medical Research, and the Department of Medicine, Monash University, Clayton, Victoria, Australia.
  1. Address correspondence and reprint requests to Peter J. Fuller, BMedSci, MBBS, PhD, FRACP, PHI Institute of Medical Research, 27-31 Wright St, Clayton, Victoria 3168, Australia. E-mail: Peter.Fuller{at}princehenrys.org.

Abstract

Objective Granulosa cell tumors of the ovary (GCTs) represent a specific subset of malignant ovarian tumors, of which there are 2 distinct subtypes, the juvenile and the adult form. Aside from surgery, no reliable therapeutic options currently exist for patients with GCT. This study sought to investigate the potential role of small molecule tyrosine kinase inhibitors (TKIs) as novel therapeutics in the clinical management of GCT.

Materials and Methods Using TKI with distinct but overlapping multitargeted specificities, cellular proliferation, viability, and apoptosis were evaluated in 2 human GCT-derived cell lines, COV434 and KGN.

Results Sunitinib, which targets the imatinib-inhibited tyrosine kinases of VEGFR, KIT, PDGFR, and FLT-3, was without effect in COV434 and KGN cell lines. Sorafenib, which has a high affinity for RAF1 and BRAF, dose dependently inhibited cellular proliferation and viability in both cell lines at concentrations equivalent to that seen in other systems. A RAF1 kinase inhibitor was without effect, suggesting that sorafenib is acting via inhibition of BRAF, or that aberrant signaling originates upstream of BRAF in the MAPK pathway. In the presence of a selective Src family inhibitor (SU6656), cell proliferation and cell viability responses dissociated; that is, although SU6656 dose dependently inhibited cell viability, it had limited effect on proliferation and apoptosis.

Conclusions These findings implicate BRAF in the activated signaling responsible for the growth and viability of GCT and suggest that TKI already in clinical use may be a therapeutic option in the treatment of GCT.

  • Granulosa cell tumor
  • Ovary
  • Molecular pathogenesis
  • Tyrosine kinase inhibitor
  • KGN
  • COV434
  • ABL - Abelson murine leukemia viral oncogene homolog
  • AP-1 - activator protein 1
  • ATP - adenosine triphosphate
  • CML - chronic myelogenous leukemia
  • EGFR - epidermal growth factor receptor
  • GCT - granulosa cell tumor of the ovary
  • HUVEC - human umbilical vein endothelial cell line
  • NFκB - nuclear factor κB
  • PDGFR - platelet-derived growth factor receptor
  • RTK - receptor tyrosine kinase
  • SCFR - Mast/stem cell growth factor receptor
  • TK- tyrosine kinase
  • TKI - tyrosine kinase inhibitor
  • VEGF - vascular endothelial growth factor
  • VEGFR - vascular endothelial growth factor receptor

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Footnotes

  • Supported by grants-in-aid from the Cancer Council Victoria, the National Australia Bank Ovarian Cancer Research Foundation, the Granulosa Cell Tumor of the Ovary Foundation, and the National Health and Medical Research Council of Australia through a Senior Principal Research Fellowship to P.J.F. (#1002559) and a Dora Lush Biomedical Postgraduate Research Scholarship to S.J. (#441132). S.J. was also in receipt of a Faculty of Medicine Postgraduate Excellence Award from Monash University. MIMR-PHI Institute of Medical Research is supported by the Victorian Government’s Medical Research Operational Infrastructure Support program. PHI Internal Data Audit #13–24.

  • The authors declare no conflicts of interest.

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