American Research Journal of Oncology

Malignant melanomas are the most lethal skin malignancy, notorious for aggressive growth and resistance to therapy. While the response to selective BRAF and MEK inhibitors (BRAFi, MEKi), alone and in combination, in BRAF V600-mutant melanoma is encouraging, virtually all patients rapidly develop secondary resistance. We have shown that constitutive deregulation of both BRAF-MEK-ERK and p16INK4A-CDK4/6-RB pathways occur at high frequencies in melanomas, and that suppression of BRAF/MEK, or restoration of p16INK4A expression/inhibition of CDK4/6 can block the growth melanoma cells, and simultaneous correction of both BRAF-MEK and p16INK4A-CDK4/6 compounds this effect and also triggers significant apoptosis in melanoma cells. Our data suggests that BRAF-MEK-ERK and p16INK4A-CDK4/6-RB pathways may act additively or synergistically in the malignant growth of melanoma cells, and could be jointly targeted for treatment of melanoma. We also reported that the expression of K-type human endogenous retrovirus (HERV-K) correlates with ERK activation and p16INK4A loss in melanoma cells, and can be inhibited by MEK and CDK4/6 inhibitors, especially in combination. Given that HERV-K may destabilize the genome and act downstream of BRAF-MEK and CDK4/6, we hypothesize that cells with activated HERV-K may escape the therapeutic effects of BRAF-MEK and CDK4/6 blockers, and that triple inhibition of BRAF-MEK, CDK4/6, and HERV-K should be an effective therapy for melanomas.