Treatments for inhibiting development and progression of nevi and melanoma having braf mutations

摘要

Disclosed herein are activating mutations in the BRAF gene that promote nevi and melanoma proliferation. These mutations produce an activated form of B­Raf, a serine/threonine kinase participant in the Ras/Raf/MEK/ERK MAPK pathway. In one example of the activating BRAF mutations, a 1796 T → A transversion produces a V599E mutated form of B-Raf. This mutated form of B-Raf possesses a tenfold greater basal kinase activity and induces focus formation in NIH3T3 cells 138 times more efficiently than does wild type B-Raf. Methods of diagnosing BRAF mutations in a subject, methods of treating nevi and melanoma in subjects having BRAF mutations, methods of selecting treatments, methods of screening for agents that influence B-Raf activity, and methods of influencing the expression of BRAF or BRAF variants are also described. Nucleotide sequences for use in the described methods are also provided, as are protein-specific binding agents, such as antibodies, that bind specifically to at least one epitope of a B-Raf variant protein preferentially compared to wild type B-Raf.