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Human Melanoma Cytolysis by Combined Inhibition of Mammalian Target of Rapamycin and Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor-2

¹ Department of Surgery, Division of Surgical Oncology, University of Virginia School of Medicine; ² Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia; ³ Center for Cell Signaling, University of Virginia Health System, Charlottesville, Virginia; ⁴ Department of Immunology, Institute for Cell Biology, Eberhard Karls University, Tuebingen, Germany; and ⁵ Departments of Surgical Oncology and Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Craig L. Slingluff, Jr., Joseph Helms Farrow Professor of Surgery, Human Immune Therapy Center, University of Virginia School of Medicine, Room 1352, Jordan Hall, P.O. Box 801457, Charlottesville, VA 22908. Phone: 434-243-2611; Fax: 434-982-3276; E-mail: cls8h{at}virginia.edu.

Key Words: VEGF • VEGFR-2 • mTOR • melanoma • bevacizumab • rapamycin

Vascular endothelial growth factor (VEGF) plays a vital role in tumor angiogenesis. VEGF is produced by human melanomas, and the VEGF receptor 2 (VEGFR-2) is expressed by most advanced stage melanomas, suggesting the possibility of an autocrine loop. Here, we show that bevacizumab, an anti-VEGF antibody, inhibits proliferation of VEGFR-2⁺ melanoma cell lines by an average of 41%; however, it failed to inhibit proliferation of VEGFR-2^neg melanoma cell lines. The growth inhibitory effect of bevacizumab was eliminated by VEGFR-2 knockdown with small interfering RNA, showing that VEGF autocrine growth in melanoma is mediated through VEGFR-2. However, bevacizumab inhibition of autocrine signals did not completely inhibit cell proliferation nor cause cell death. Cell survival is mediated partially through mammalian target of rapamycin (mTOR), which is inhibited by rapamycin. Combination of bevacizumab with rapamycin caused loss of half of the VEGFR-2⁺ melanoma cells, but no reduction in the number of VEGFR-2^neg melanoma cells. The results show (a) an autocrine growth loop active in VEGFR-2⁺ melanoma, (b) a nonangiogenic mechanism for inhibition of melanoma by blocking autocrine VEGFR-2 activation, and (c) a possible therapeutic role for combination of inhibitors of mTOR plus VEGF in selected melanomas. [Cancer Res 2008;68(11):4392–7]