BRAF and MEK Gene Rearrangements in Melanoma: Implications for Targeted Therapy
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REVIEW ARTICLE
BRAF and MEK Gene Rearrangements in Melanoma: Implications for Targeted Therapy Pedro Madureira • Ramon Andrade de Mello
Ó Springer International Publishing Switzerland 2014
Abstract The incidence of melanoma has been continuously increasing in the last decades, and faster than any other cancers. Melanoma is the leading cause of death from skin disease. It is estimated that 76,690 Americans will be diagnosed with melanoma in 2013 and 9,480 will die from the disease. Molecular mechanisms underlying melanoma pathogenesis have been extensively studied and novel therapeutic weapons developed. BRAF and MEK pathways emerged as key players in this field. Recently, novel drugs such as vemurafenib, dabrafenib and trametinib were approved for treatment of advanced disease harbouring BRAF V600E and V600K mutations. In addition, an effective strategy to build upon the successes seen with dabrafenib and trametinib monotherapies has been to combine these agents (CombiDT), with the goal of further improving response rates and delaying resistance. Our
P. Madureira ICBAS-Instituto de Cieˆncias Biome´dicas Abel Salazar, University of Porto, Porto, Portugal P. Madureira IBMC-Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal R. A. de Mello Department of Medicine, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal R. A. de Mello (&) Department of Medical Oncology, Portuguese Oncology Institute (IPO PORTO), Rua Dr. Antonio Bernardino de Almeida, 4200-072 Porto, Portugal e-mail: [email protected]; [email protected] R. A. de Mello Department of Medicine and Biomedical Sciences, School of Medicine, University of Algarve, Faro, Portugal
review gives an overall point of view concerning BRAF and MEK pathways as well as the role of BRAF and MEK testing in directing the personalised treatment of patients with metastatic melanoma.
1 Introduction The incidence of melanoma has been continuously increasing in the last decades, and faster than any other cancers [1, 2]. Cutaneous melanoma is most common in high-income countries with large numbers of Caucasians, while it is rare and presents with a different phenotype and histology in low- or middle-income countries and in other ethnic groups [3, 4]. Metastatic melanoma is the most fatal of cancers, with a 5-year survival rate of less than 10 % [5]. Although ultraviolet radiation (UVR) is the major known aetiologic agent associated with melanoma, different patterns of sun exposure have different effects in the development of melanoma. In fact, long-term sun exposure does not increase the risk for melanoma and is even associated with inhibition of melanoma [6, 7]. On the other hand, intermittent sun exposure is the major form of UVR promoting the development of melanoma [8, 9]. Currently, the number of new cases of melanoma per year is about 160,000, with an overall mortality rate of approximately 25 %. In high-income countries, melanoma has an incidence of 9.5/100,000 men and 8.6/100,000 women [10, 11]. The majority of melanomas a
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