*5.1. Resistance to MAPK Inhibitors (MAPKi)*

Genomic profiling of CMs revealed several actionable mutations in tumors that may be matched with targeted therapies. Recurrent driver alterations such as BRAF V600, NRAS, and NF-1 facilitated the design of BRAF inhibitors (BRAFi: vemurafenib and dabrafenib) and MEKi (trametinib, cobimetinib, and binimetinib) that have significantly improved patient OS [5,6]. Although 60–80% of BRAF-mutated CM patients respond well

to targeted therapy, a significant proportion of them develop resistance, which results in life-threatening metastases and death [109,148,149]. The phenomenon of MAPKi resistance is complex and multifactorial and involves, among others, alterations of the BRAF V600E gene (amplification, aberrant splicing) [150–152], which leads to MAPK pathway hyperactivation, mutations that activate alternative survival pathways [153], modifications in apoptotic machinery [154], RTK hyperactivation [155,156], and the presence of slowcycling populations [147], to which are added other MITFs, c-AMP, and NF-kB related mechanisms [9]. In CM, tumor refractoriness has been extensively linked with genetic alterations in many cancer-related genes; however, in some cases, the cause of the resistance appears to be non-genetic in nature [157]. Peculiarities such as the rapid kinetics and the transient nature of refractory phenotypes suggest the existence of an epigenetic basis for drug resistance in CM, pointing out that epigenetic remodeling is a fundamental feature of tumor development and adaptation to therapy [157,158]. Therefore, new therapeutic targets and therapies are critically necessary to improve the therapeutic management of CM. In this section, epigenetic alterations associated with MAPKi resistance and how they can be exploited in the future to become therapeutic targets and biomarkers in CM will be highlighted.
