The development of targeted therapies for non- p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in , , or form 10% of human melanomas and are heterogeneous in their genomic drivers. mutations are enriched in -mutant melanoma and function as an innate or adaptive resistance mechanism to BRAF inhibition. Here we report the case of a patient with TWT melanoma with a bona fide mutation without any mutations. We performed a structural analysis to validate that the MEK inhibitor trametinib could block this mutation. Although the patient initially responded to trametinib, he eventually progressed. The presence of a deletion prompted us to combine a CDK4/6 inhibitor, palbociclib, with trametinib but without clinical benefit. Genomic analysis at progression showed multiple novel copy number alterations. Our case illustrates the challenges of combining MEK1 and CDK4/6 inhibitors in case of resistance to MEK inhibitor monotherapy.