Recent Developments in Targeting the Cell Cycle in Melanoma

Melanoma is an aggressive cancer with rising incidence, particularly among older individuals. Despite advancements in targeted therapies for BRAF and MEK proteins and immunotherapies, many patients either fail to respond or develop resistance. For those progressing on immunotherapy, limited treatment options remain. The Cyclin D-CDK4/6-RB pathway is commonly dysregulated in melanoma, with up to 90% of cases showing alterations that activate it. Although targeting Cyclin-CDK complexes has shown promise in preclinical models, clinical responses have been suboptimal. This review explores the molecular mechanisms behind Cyclin-CDK dysregulation in melanoma and the challenges of targeting this pathway. It also discusses strategies to improve the efficacy of CDK4/6 inhibitors, including combination therapies to overcome resistance and enhance patient outcomes. Understanding these mechanisms can guide the development of more effective treatments for melanoma.