Journal
PIGMENT CELL & MELANOMA RESEARCH
Volume 27, Issue 4, Pages -Publisher
WILEY
DOI: 10.1111/pcmr.12242
Keywords
melanoma therapy; drug resistance; intrinsic apoptosis pathway; BH3-mimetic; MCL-1 antagonist; IAP antagonist; SMAC-mimetic
Categories
Funding
- Malaysian Government
- Cancer Institute New South Wales
- Cancer Council NSW [RG 09-08, RG 13-06]
- Cancer Australia/Cure Cancer Australia Foundation [570778]
- Cancer Institute New South Wales [08/RFG/1-27]
- National Health and Medical Research Council Australia [1003637]
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Melanoma drug resistance is often attributed to abrogation of the intrinsic apoptosis pathway. Targeting regulators of apoptosis is thus considered a promising approach to sensitizing melanomas to treatment. The development of small-molecule inhibitors that mimic natural antagonists of either antiapoptotic members of the BCL-2 family or the inhibitor of apoptosis proteins (IAPs), known as BH3- or SMAC-mimetics, respectively, are helping us to understand the mechanisms behind apoptotic resistance. Studies using BH3-mimetics indicate that the antiapoptotic BCL-2 protein MCL-1 and its antagonist NOXA are particularly important regulators of BCL-2 family signaling, while SMAC-mimetic studies show that both XIAP and the cIAPs must be targeted to effectively induce apoptosis of cancer cells. Although most solid tumors, including melanoma, are insensitive to these mimetic drugs as single agents, combinations with other therapeutics have yielded promising results, and tests combining them with BRAF-inhibitors, which have already revolutionized melanoma treatment, are a clear priority.
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