Nras in melanoma: Targeting the undruggable target

•Ras proteins are crucial crossroads of signaling pathways leading to the control of proliferation, apoptosis and differentiation.•Currently, mutations in NRAS, KRAS and HRAS are known to be present in 20%, 2% and 1% of all melanomas, respectively.•In BRAF mutated melanoma patients, a concomitant baseline mutation in the upstream NRAS oncogene may result in early lack of clinical benefit to BRAF inhibitors.•RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors.•NRAS has so far proven to be intractable to conventional drug discovery, and represents an unmet medical need in melanoma management.

RAS belongs to the guanosine 5′-triphosphate (GTP)-binding proteins’ family, and oncogenic mutations in codons 12, 13, or 61 of RAS family occur in approximately one third of all human cancers with N-RAS mutations found in about 15–20% of melanomas. The importance of RAS signaling as a potential target in cancer is emphasized not only by the prevalence of RAS mutations, but also by the high number of RAS activators and effectors identified in mammalian cells that places the RAS proteins at the crossroads of several, important signaling networks. Ras proteins are crucial crossroads of signaling pathways that link the activation of cell surface receptors with a wide variety of cellular processes leading to the control of proliferation, apoptosis and differentiation. Furthermore, oncogenic ras proteins interfere with metabolism of tumor cells, microenvironment's remodeling, evasion of the immune response, and finally contributes to the metastatic process. After 40 years of basic, translational and clinical research, much is now known about the molecular mechanisms by which these monomeric guanosine triphosphatase-binding proteins promote cellular malignancy, and it is clear that they regulate signaling pathways involved in the control of cell proliferation, survival, and invasiveness. In this review we summarize the biological role of RAS in cancer by focusing our attention on the biological rational and strategies to target RAS in melanoma.