BRAF, a target in melanoma

Abstract

The successful translation of therapies targeting signal-transduction pathways that are activated by oncogenes has provided a model for molecularly targeted therapy, and the identification of mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF), a serine/threonine kinase, has turned the attention of the melanoma field toward this concept. The current review indicated that BRAF represents an important target in cancer, in part because it is present in 7% of all cancers and also because it represents the first intracellular signaling molecule that is activated by point mutations for which single-agent therapy appears to have efficacy. Therapy for advanced melanoma has progressed slowly over the past 3 decades, although significant advances have been made in other cancers with the application of cytotoxic chemotherapy and targeted therapies. However, in melanoma, cytotoxic chemotherapies have severe limits, chemotherapy does not convincingly improve on the natural history of metastatic disease and has no role in the adjuvant setting, and cytokine therapy may have a niche in both the adjuvant and metastatic settings but confers only a modest benefit to a small proportion of patients at the cost of severe toxicity. Thus, there are few other cancers in which completely novel therapies are so highly prioritized in clinical research. Understanding network of signal-transduction pathways and how that network may adapt to BRAF inhibition or mitogen-activated protein kinase kinase inhibition will point to the next generation of clinical trials investigating rational combination regimens. The current investigations in melanoma will create a set of hypotheses to be tested in each cancer that harbors BRAF mutations. Cancer 2010;116:4902-13. V C 2010 American Cancer Society.KEYWORDS: BRAF, melanoma, oncogene, kinase inhibitor, mutation.Therapy for advanced melanoma has progressed slowly over the past 3 decades, whereas significant advances have been made with the application of cytotoxic chemotherapy and, more recently, targeted therapies in other cancers. The application of cytotoxic chemotherapies that have disease-altering ability in other cancers has severe limits in melanoma. Chemotherapy does not convincingly improve upon the natural history of metastatic disease and has no role in the adjuvant setting. Cytokine therapy has a niche in both the adjuvant and metastatic settings but confers a modest benefit to a small proportion of patients at the cost of severe toxicity. Thus, there are few other cancers in which completely novel therapies are so highly prioritized in clinical research. The successful translation of therapies targeting signal-transduction pathways that are activated by oncogenes has provided a model for molecularly targeted therapy. The identification of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in 2002 was the watershed event that turned the attention of the melanoma field to this concept. 1 BRAF BiologyRaf kinases are components of the mitogen-activated protein (MAP) k...

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“…This mutation is activating in melanoma and confers sensitivity to BRAF inhibition. 42 To our knowledge, this mutation has not been described in CLL prior to this report. Further studies assessing the role of BRAF inhibitors in patients with CLL who harbor BRAF mutations are warranted.…”

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“…BRAF is mutated in approximately 50% of melanomas; 80–90% of these activating mutations involve a single substitution of valine in position 600 with glutamic acid (V600E) (18). Additional, more rare, BRAF mutations include V600K (valine substituted with lysine) and V600D (valine substituted with aspartic acid) (19).…”

Molecular Targeted Therapy in Melanoma: A Way to Reverse Resistance to Conventional Drugs

“…In melanoma is estimated that the prevalence of BRAF mutation is between 30% and 70%. The most common BRAF mutation is the T1796A point mutation, that results in a substitution of glutamic acid (E) for valine (V) at position 600 of the aminoacid sequence in exon 15 while the other mutations observed, like the ''V600E'' substitution, interest the kinase domain of the protein [72]. This mutation introduces, in the kinase domain, a conformational change in protein structure, leading to protein constitutive activation and increase of its basal kinase activity [1].…”

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