BH3-only proteins: possible proapoptotic triggers for melanoma therapy.

Despite recent developments for new targeted therapies in melanoma, as BRAF inhibitors and immune-stimulating antibodies, tumor relapse frequently follows within less than a year. Therapy resistance is explained by defects in proapoptotic signalling. Thus, efficient induction of apoptosis in tumor cells appears as predominant therapeutic goal. In apoptosis control of melanoma, the balance between pro- and antiapoptotic Bcl-2 proteins plays a decisive role. In particular, members of the subfamily of BH3-only proteins function as proapoptotic triggers, and mimetics of these proteins are already in clinical trials in other cancers. Recent experimental work has revealed that the effects of different treatments in melanoma are related to the activation of BH3-only proteins, and also the proapoptotic effects of BRAF inhibitors are prevented by knockdown of the BH3-only protein Bim. Thus, melanoma therapy might be critically improved by the combination of survival pathway antagonists as BRAF inhibitors with BH3 mimetics.