Targeted therapy for V600 BRAF mutant solid tumors already exists but resistance to the treatment is still a serious problem to be solved. Moreover, there are currently no approved targeted therapeutic options against non-V600 BRAF mutant tumors. Here we studied targeted therapy resistance mechanisms of V600 BRAF mutant melanoma and also explored potential alternative solutions for their treatment. In V600 BRAF mutant melanoma cells that did not or slightly express PTEN protein, prenylation inhibitor zoledronic acid inhibited cell proliferation and induced apoptosis more profoundly than in melanoma cells expressing PTEN. We also investigated the proliferation and migration of pre- and posttreatment isogeneic melanoma cell line pairs. Posttreatment V600 BRAF mutant melanoma cells showed more invasive phenotype. We found that migration and proliferation showed a negative correlation with MITF and FRA-1 mRNA levels, respectively. Both transcription factors correlated with EGFR mRNA expression. Finally, in non-V600 BRAF mutant cell lines combined inhibition of pan-RAF and MEK with sorafenib/AZ628 and selumetinib showed significantly stronger cell growth, cell migration and Erk activation inhibition and also increased apoptosis induction compared to single treatments.