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.
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