The window of opportunities for targeted therapy in BRAFwt/NRASwt/KITwt melanoma: biology and clinical implications of fusion proteins and other mutations.

Treatment options in advanced melanoma have been subject to a major change over the last years. The discovery of the oncogenic point mutation BRAFV600E and subsequently developed BRAF inhibitors had a major impact on patient's survival. Further important mutations have been found in the NRAS gene, although not yet druggable, and others involve c-kit in acral and mucosal melanoma. Imatinib was shown to achieve high response rates in c-kit mutated melanoma. Despite good response rates in these targeted therapies and introduction of immunotherapy, there are still patients left, who develop resistance upon therapy or patients without the option of targeted therapy. Therefore it is necessary to identify further therapeutic options for this subset of patients. Several new mutations have been described so far that might be suitable for targeted therapy or useful as clinical biomarkers. Alterations in various receptor tyrosine kinases lead to constitutively activated downstream signaling and might be responsible for non-response to common therapies. In contrast, tyrosine kinase inhibitors such as sunitinib or nilotinib could be suitable for patients harboring those alterations. Additionally, chromosomal rearrangements have been described in many different cancer types, resulting in oncogenic fusion proteins that involve BRAF, ROS1, NTRK, ALK and others. These are an emerging therapeutic field, especially in spitzoid melanomas. Further mutations have been detected in the neurofibromin 1 and RAC1 gene, although the clinical relevance is still not fully revealed. Within this review we will summarize the current evidence and focus on possible further upcoming targets and therapeutic opportunities in BRAFwt/NRASwt/KITwt melanoma.