The pleiotropic mechanism of Rac1-driven BRAFi/MEKi resistance, together with the difficulty of targeting the Rac1 effector PAK family kinases, creates a significant challenge for treating BRAF-mutant melanomas that develop Rac1-driven resistance to BRAF/MEK-targeted second line therapies after progression on front line immunotherapy. The gene discussed is BRAF; the disease is melanoma.