Simultaneous inhibition of MEK and CDK4 leads to potent apoptosis in human melanoma cells

Deregulation of RAS-RAF-MEK-ERK and p16INK4A-cycylin D:CDK4/6-RB pathways is important for melanoma development. Chemotherapeutic agents targeting both pathways were developed but results of clinical studies with monotherapies were disappointing. We examined the effect of cotargeting both pathways with MEK inhibitor PD98059 and CDK4 inhibitor 219476 on human melanoma cells lines, and found that combinatorial treatment dramatically increased apoptosis compared to the single agent treatment. The apoptosis was associated with downregulation of BCL2, BCL2L1, BIRC5, and upregulation of BIM. Our results indicate that simultaneously targeting ERK and RB pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations.