[Future targeting of the RAS/RAF/MEK/ERK signaling pathway in oncology: the example of melanoma].

The proliferation, survival and mobility of cancer cells are maintained by deregulation of signaling pathways, including RAS/RAF/MEK/ERK/. Constitutive activation of these pathways is a common event in human cancers. It is most often caused by mutations or altered expression of genes encoding key players in this pathway. Knowledge of the mechanisms of intracellular activation of these circuits has led to the development of inhibitory molecules aimed at limiting tumor growth. These molecules have been developed through extensive clinical trials marked by impressive therapeutic successes that have pioneered the concept of targeted therapies, leading to a new paradigm of cancer therapy. However, despite these remarkable clinical responses, particularly in metastatic melanoma, poorly understood drug resistance mechanisms eventually come into play. Resistance mechanisms associated with secondary mutations in B-RAF seem to be infrequent in melanomas, while those related to target circumvention are more common. The latter include an increase in the expression and regulation of PDGF and IGF-l receptors, and secondary mutations in the N-RAS, COT or MEK genes. They involve the activation pathways MEK/ERK and/or PI3K/AKT in conditions in which the target is inhibited. Resistance may also be explained by deregulation of the MEK/ERK pathway, leading to the expression of genes that had been subject to negative feedback. Moreover, the tumor microenvironment, through the secretion of soluble factors, stimulates signaling pathways that can compensate for MEK/ERK pathway inhibition. Lastly, combinations of MEK/ERK inhibition and immunotherapy open the way to new therapeutic strategies designed to circumvent drug resistance. Without calling into question the concept of "oncogenic addiction", in which alteration of a single gene is responsible for persistence of the tumoral phenotype, these findings call for a rethink on the use of targeted therapies. A more integrated view of the tumor including its microenvironment, will no doubt be necessary.