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Imatinib Mesylate (Gleevec) Inhibits Ovarian Cancer Cell Growth through a Mechanism Dependent on Platelet-Derived Growth Factor Receptor and Akt Inactivation

¹ Departments of Medicine, ² Obstetrics and Gynecology, ³ Microbiology and Immunology, ⁴ Walther Oncology Center, ⁵ Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana; and ⁶ Departments of Medicine, ⁷ Microbiology, Immunology and Molecular Genetics; and ⁸ Jonsson Comprehensive Cancer Center, University of California, David Geffen School of Medicine, Los Angeles, California

Purpose: We identified the platelet-derived growth factor receptor (PDGFR) as an ovarian cancer-specific gene by microarray hybridization using primary cultures. The purpose of this study is to evaluate whether disruption of the platelet-derived growth factor-regulated growth pathway by Imatinib mesylate (Gleevec), a partially selective PDGFR inhibitor, inhibits growth of ovarian cancer cells expressing PDGFR.

Experimental Design: To investigate the effects of Imatinib mesylate in ovarian cancer, we established an in vitro model by immortalizing primary ovarian cells, which express endogenous PDGFR, and we evaluated the effects of Imatinib on cell proliferation. In addition, we investigated the involvement of Akt in mediating Imatinib-inhibited cell growth inhibition.

Results: We found that 39% of ovarian tumors express PDGFR by immunohistochemistry. We showed that Imatinib inhibits the growth of ovarian cancer cells in a PDGFR-specific manner, at clinically relevant concentrations (IC₅₀ < 1 µM). Imatinib inhibits the growth of three primary ovarian cultures and two immortalized cultures (PDGFR positive), but has no effects on SkOv3 and CaOv3 cell lines (PDGFR negative). Imatinib exerts antiproliferative effects by arresting cells at G₀-G₁ and preventing progression through S phase. Imatinib inhibits both PDGFR and Akt phosphorylation at a concentration of 1 µM. Stable expression of constitutively active Akt induces partial resistance to PDGFR inhibition in ovarian cancer cells, as demonstrated by cell proliferation assay and cell cycle analysis.

Conclusions: Our data indicate that Imatinib mesylate inhibits the growth of ovarian cancer cells through PDGFR inactivation. In addition, our results suggest that constitutive Akt activation modulates sensitivity to Imatinib in ovarian cancer cells.

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