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Targeting the intrinsic apoptosis pathway as a strategy for melanoma therapy

Lookup NU author(s): Dr David Hill


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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.

Publication metadata

Author(s): Mohana-Kumaran N, Hill DS, Allen JD, Haass NK

Publication type: Review

Publication status: Published

Journal: Pigment Cell & Melanoma Research

Year: 2014

Volume: 27

Issue: 4

Pages: 525-539

Print publication date: 01/07/2014

Online publication date: 09/04/2014

Acceptance date: 17/03/2014

ISSN (print): 1755-1471

ISSN (electronic): 1755-148X



DOI: 10.1111/pcmr.12242