Crosstalk signaling in targeted melanoma therapy

Inhibition of the BRAF/MAPK pathway belongs to the standard therapies for patients with activating BRAF^V600E/K mutations. However, even in well-responding tumors, anti-tumorigenic effect and clinical benefit are only transient, and the original tumors often relapse. This demonstrates that there are remaining residual tumors, which have withstood therapy-induced apoptosis and which have the potential to resume growth. Although BRAF mutant melanoma cells seem to depend on BRAF/MAPK signaling, the inhibition of this pathway triggers several events, which modulate the tumor as well as the tumor niche. After a certain adaptation period, this can turn out to be beneficial for tumor growth and metastasis-even in cases of good initial tumor response. This review sheds light on the biology of BRAF/MEK inhibitor-sensitive melanoma cells, which survive targeted therapy and will address the crosstalk signaling events occurring in BRAF mutant melanomas when the BRAF/MAPK pathway is fully blocked. The knowledge of these events is important for potential future drug combinations, which enhance the inhibitory effect of BRAF/MEK inhibition, particularly in patients not eligible for immune therapy.