Abstract
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 “druggable” 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.
Highlights
Malignant skin melanoma is one of the most chemoresistant and aggressive human neoplasias
This is the beginning of a novel class of drugs in metastatic melanoma; the identification of the transduction signaling networking and other “druggable” kinases is in active research
We reviewed the research advances in signaling pathway inhibition and new strategies to metastatic melanoma treatment
Summary
Malignant skin melanoma is one of the most chemoresistant and aggressive human neoplasias. Other compounds like MK-2206 [57, 58], RX0201, PBI-05204, and GSK2141795 [59] are in early clinical development for several types of cancer [60,61,62,63] It has been observed, in preclinical models, a cytotoxic synergistic effect of the combination of MK-2206 with other target therapies and conventional chemotherapy [58]. In preclinical models, a cytotoxic synergistic effect of the combination of MK-2206 with other target therapies and conventional chemotherapy [58] This approach could be promising in malignant melanomas harboring the BRAF mutation, taking into account the role played by the interaction of those kinases in the malignant transformation. A number of phase I and -II studies testing the combination of everolimus and temsirolimus with conventional cytotoxic therapies are currently being carried out [77]
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