Plötz Michael, Eberle Jürgen
Department of Dermatology, Venerology and Allergology, HTCC - Skin Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Exp Dermatol. 2014 Jun;23(6):375-8. doi: 10.1111/exd.12399.
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.
尽管黑色素瘤的新型靶向治疗有了新进展，如BRAF抑制剂和免疫刺激抗体，但肿瘤复发通常在不到一年的时间内就会出现。治疗耐药性是由促凋亡信号通路的缺陷所解释的。因此，在肿瘤细胞中有效诱导凋亡似乎是主要的治疗目标。在黑色素瘤的凋亡控制中，促凋亡和抗凋亡Bcl-2蛋白之间的平衡起着决定性作用。特别是，仅含BH3结构域蛋白亚家族的成员作为促凋亡触发因子发挥作用，这些蛋白的模拟物已在其他癌症的临床试验中。最近的实验工作表明，黑色素瘤中不同治疗方法的效果与仅含BH3结构域蛋白的激活有关，并且BRAF抑制剂的促凋亡作用也可通过敲低仅含BH3结构域蛋白Bim来阻止。因此，将生存信号通路拮抗剂如BRAF抑制剂与BH3模拟物联合使用可能会显著改善黑色素瘤的治疗。
