%0 Journal Article
%T Targeting the Cellular Signaling: BRAF Inhibition and Beyond for the Treatment of Metastatic Malignant Melanoma
%A Felipe Ades
%A Otto Metzger-Filho
%J Dermatology Research and Practice
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/259170
%X Although advances in cytotoxic treatments have been obtained in several neoplasias, in metastatic melanoma there was no drug able to significantly change the natural history of the disease in the last 30 years. In the last decade, translational research identified important mechanisms in malignant transformation, invasion, and progression. Signaling pathways can be abnormally activated by oncogenes. The identification of oncogenic mutated kinases implicated in this process provides an opportunity for new target therapies. The melanoma dependence on BRAF-mutated kinase allowed the development of inhibitors that produced major responses in clinical trials. This is the beginning of a novel class of drugs in metastatic melanoma; the identification of the transduction signaling networking and other ˇ°druggableˇ± kinases is in active research. In this paper, we discuss the ongoing research on cellular signaling inhibition, resistance mechanisms, and strategies to overcome treatment failure. 1. Introduction Malignant skin melanoma is one of the most chemoresistant and aggressive human neoplasias. In the last 30 years, no cytotoxic agent was able to importantly change the natural history of disease [1]. Several strategies to overcome resistance to cytotoxic agents have been tested, including combinations of drugs [2], cytokines, and vaccination [1]. With these therapeutic approaches, only a small fraction of the metastatic patients experienced tumour shrinkage, but such effects did not translate into significant clinical benefits in terms of progression-free survival or overall survival [1, 3]. Until recently, no predictive marker of response could be established. This scenario started to change in the last decade. With advances in translational research, it was possible to identify pathways and somatic mutations implicated in the biology of the melanoma. The identification and blockade of abnormal signaling through the mitogen-activated protein kinase (MAPK) pathway is the most promising therapeutic strategy to date. Around 60% of all melanomas express somatic mutations in the BRAF protein, and 90% of these express the oncogenic activating V600E mutation [4]. Vemurafenib, an inhibitor of the V600E BRAF kinase activity, has produced major responses [5] and showed an overall survival advantage as single agent against dacarbazine in a recent phase III trial [6]. Despite the advances, responses are transitory and we have not yet been able to neither cure nor stabilize the disease for long periods. Better understanding of tumoral biology and its adaptations to the
%U http://www.hindawi.com/journals/drp/2012/259170/