Paper of the Month - March, 2011

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Inhibition of mutated, activated BRAF in metastatic melanoma.

Flaherty KT, Puzanov I, Kim KB et al.
Editor’s note: Metastatic melanoma is associated with a high mortality rate. Treatment with either high-dose interleukin-2 or dacarbazine is associated with response rates of up to 20%, with only a small percentage of patients achieving a complete response and with no impact on overall survival (Cancer Treat Rep 1976;60:165–76; J Clin Oncol 1999;17:2105–16; J Clin Oncol 2000;18:158–66 [Erratum, J Clin Oncol 2000;18:2351]; J Clin Oncol 2006;24:4738–45). Up to 60% of melanomas have been shown to have an activating mutation of the serine–threonine protein kinase B-RAF (BRAF); 90% of reported BRAF mutations result in the substitution of glutamic acid for valine at amino acid 600 (V600E mutation). This mutation causes activation of the MAP kinase pathway. PLX4032, manufactured by Roche Pharmaceuticals, inhibits BRAF with the V600E mutation thus diminishing signaling through the MAP kinase pathway and blocking proliferation of cells.