Potential Biomarkers of Skin Melanoma Resistance to Targeted Therapy-Present State and Perspectives

Melanoma is the most aggressive skin cancer, the number of which is increasing worldwide every year. It is completely curable in its early stage and fatal when spread to distant organs. In addition to new therapeutic strategies, biomarkers are an important element in the successful fight against this cancer. At present, biomarkers are mainly used in diagnostics. Some biological indicators also allow the estimation of the patient's prognosis. Still, predictive markers are underrepresented in clinics. Currently, the only such indicator is the presence of the V600E mutation in the BRAF gene in cancer cells, which qualifies the patient for therapy with inhibitors of the MAPK pathway. The identification of response markers is particularly important given primary and acquired resistance to targeted therapies. Reliable predictive tests would enable the selection of patients who would have the best chance of benefiting from treatment. Here, up-to-date knowledge about the most promising genetic and non-genetic resistance-related factors is described. These are alterations in MAPK, PI3K/AKT, and RB signaling pathways, e.g., due to mutations in NRAS, RAC1, MAP2K1, MAP2K2, and NF1, but also other changes activating these pathways, such as the overexpression of HGF or EGFR. Most of them are also potential therapeutic targets and this issue is also addressed here.