Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRα, and PDGFRβ in ovarian cancers

Most women with epithelial ovarian cancer are diagnosed with advanced disease. Despite surgery and initial tumor reduction by standard chemotherapy, the tumors frequently recur and the patients eventually die of their disease. New drugs that inhibit tyrosine kinase receptors (TKRs) are being investigated for treatment and this study was undertaken to determine the expression and mutational state for 3 TKRs (c-kit, platelet-derived growth factor receptor [PDGFR] α, and PDGFRβ) in ovarian cancer. Tissue arrays containing 84 epithelial ovarian tumors were studied by immunohistochemistry with antibodies specific for c-kit, PDGFRα, and PDGFRβ. Immunoreactivity was detected in 78% of the tumor to at least one TKR. PDGFRα was expressed in the largest percentage of ovarian tumors (58%) whereas 29% expressed PDGFRβ. Two commercial antibodies against c-kit were studied and 33% of the tumors stained with one but only 6% were interpreted as positive with the second antibody. Activation of TKRs may occur through mutations but, by sequence analysis, no mutations were detected in 6 ovarian tumors with elevated immunoreactivity for each of the TKRs (c-kit, PDGFRα, and PDGFRβ). Tyrosine kinase receptors could also be activated through autocrine or paracrine stimulation of receptor by its ligand. Of 43 (35%) tumors tested for both c-kit receptor and its ligand (stem cell factor), 15 expressed both proteins indicating the possibility that this autocrine stimulation feedback loop is a factor in the growth of some ovarian cancers. This study demonstrates that PDGFRα, PDGFRβ, and c-kit are expressed in a high percentage of epithelial ovarian cancers suggesting that tyrosine kinase inhibitors may be useful in the treatment of these tumors.