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[Cancer Research 63, 5198-5202, September 1, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

Suppression of BRAFV599E in Human Melanoma Abrogates Transformation1

Sunil R. Hingorani, Michael A. Jacobetz, Gavin P. Robertson, Meenhard Herlyn and David A. Tuveson2

Abramson Family Cancer Research Institute and Abramson Cancer Center at the University of Pennsylvania [S. R. H., M. A. J., D. A. T.] and Department of Medicine [S. R. H., D. A. T.], University of Pennsylvania and Wistar Institute [M. H.], Philadelphia, Pennsylvania 19104, and Departments of Pharmacology, Dermatology, and Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 [G. P. R.]

Activating mutations in the BRAF serine/threonine kinase are found in >70% of human melanomas, of which >90% are BRAFV599E. We sought to investigate the role of the BRAFV599E allele in malignant melanoma. We here report that suppression of BRAFV599E expression by RNA interference in cultured human melanoma cells inhibits the mitogen-activated protein kinase cascade, causes growth arrest, and promotes apoptosis. Furthermore, knockdown of BRAFV599E expression completely abrogates the transformed phenotype as assessed by colony formation in soft agar. Similar targeting of BRAFV599E or wild-type BRAF in human fibrosarcoma cells that lack the BRAFV599E mutation does not recapitulate these effects. Moreover, these results are specific for BRAF, as targeted interference of CRAF in melanoma cells does not significantly alter their biological properties. Thus, when present, BRAFV599E appears to be essential for melanoma cell viability and transformation and, therefore, represents an attractive therapeutic target in the majority of melanomas that harbor the mutation.




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