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[Cancer Research 66, 999-1006, January 15, 2006]
© 2006 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Oncogenic BRAF Is Required for Tumor Growth and Maintenance in Melanoma Models

Klaus P. Hoeflich1, Daniel C. Gray1, Michael T. Eby1, Janet Y. Tien2, Leo Wong2, Janeko Bower2, Alvin Gogineni3, Jiping Zha4, Mary J. Cole3, Howard M. Stern4, Lesley J. Murray2, David P. Davis1 and Somasekar Seshagiri1

Departments of 1 Molecular Biology, 2 Molecular Oncology, 3 Tumor Biology and Angiogenesis, and 4 Pathology, Genentech, South San Francisco, California

Requests for reprints: Somasekar Seshagiri, Genentech, Inc., 1 DNA Way MS224, South San Francisco, CA 94080. Phone: 650-225-3351; Fax: 650-225-1762; E-mail: sekar{at}gene.com.

The usual paradigm for developing kinase inhibitors in oncology is to use a high-affinity proof-of-concept inhibitor with acceptable metabolic properties for key target validation experiments. This approach requires substantial medicinal chemistry and can be confounded by drug toxicity and off-target activities of the test molecule. As a better alternative, we have developed inducible short-hairpin RNA xenograft models to examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results show that tumor regression resulting from BRAF suppression is inducible, reversible, and tightly regulated in these models. Analysis of regressing tumors showed the primary mechanism of action for BRAF to be increased tumor cell proliferation and survival. In a metastatic melanoma model, conditional BRAF suppression slowed systemic tumor growth as determined by in vivo bioluminescence imaging. Taken together, gain-of-function BRAF signaling is strongly associated with in vivo tumorigenicity, confirming BRAF as an important target for small-molecule and RNA interference–based therapeutics. (Cancer Res 2006; 66(2): 999-1006)




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Copyright © 2006 by the American Association for Cancer Research.