BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
The identification of recurrent mutations in the 600th codon of BRAF in nearly half of melanomas in 2002 by Davies et al. represented a major therapeutic opportunity . Sorafenib (Nexavar, Bayer), a putative BRAF inhibitor, was the first agent to show pre-clinical activity in BRAF mutant melanomas, partially inhibiting ERK signaling and inducing cell death . The clinical experience with this agent, however, was disappointing. In an early study, 37 unselected patients with advanced melanoma received sorafenib, with only one patient experiencing a partial response and 19% achieving temporary stable disease . Moreover, there was no correlation between disease stability and BRAF mutation status. Subsequent trials combined sorafenib with cytotoxic chemotherapy but demonstrated no advantage over chemotherapy alone and no genotype-specific effect for those patients with BRAF mutant melanoma was observed [4, 5]. The modest activity of sorafenib is now generally attributed to its anti-angiogenic properties rather than to specific inhibition of mutant BRAF. Additional clinical development of sorafenib in melanoma is not ongoing since more effective BRAF inhibitors have now been approved.
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