RAC1 and melanoma: Primary resistance mechanisms occur in approximately 50% of treatment-naïve melanoma patients [85], and are mainly associated with large intra-tumoural heterogeneity or pre-existing genetic causes: RAC1 and HOXD8 mutations [101]; MEK mutations [18]; CCND1 amplification [102]; loss of PTEN [103]; NF1 expression [104]; and mutations in the TERT promoter region [105].