Countering TRAIL Resistance in Melanoma.

Countering TRAIL Resistance in Melanoma.

Publication date: May 11, 2019

Melanoma of the skin has become a prime example for demonstrating the success of targeted cancer therapy. Nevertheless, high mortality has remained, mainly related to tumor heterogeneity and inducible therapy resistance. But the development of new therapeutic strategies and combinations has raised hope of finally defeating this deadly disease. TNF-related apoptosis-inducing ligand (TRAIL) represents a promising antitumor strategy. The principal sensitivity of melanoma cells for TRAIL was demonstrated in previous studies; however, inducible resistance appeared as a major problem. To address this issue, combination strategies were tested, and survival pathway inhibitors were shown to sensitize melanoma cells for TRAIL-induced apoptosis. Finally, cell cycle inhibition was identified as a common principle of TRAIL sensitization in melanoma cells. Mitochondrial apoptosis pathways, pro- and antiapoptotic Bcl-2 proteins as well as the rheostat consisted of Smac (Second mitochondria-derived activator of caspase) and XIAP (X-linked inhibitor of apoptosis protein) appeared to be of particular importance. Furthermore, the role of reactive oxygen species (ROS) was recognized in this setting. Inducible TRAIL resistance in melanoma can be explained by (i) high levels of antiapoptotic Bcl-2 proteins, (ii) high levels of XIAP, and (iii) suppressed Bax activity. These hurdles have to be overcome to enable the use of TRAIL in melanoma therapy. Several strategies appear as particularly promising, including new TRAIL receptor agonists, Smac and BH3 mimetics, as well as selective kinase inhibitors.

Eberle, J. Countering TRAIL Resistance in Melanoma. 22602. 2019 Cancers (Basel) (11):5.

Concepts Keywords
Apoptosis Apoptosis
Basel TRAIL
Bax XIAP
Caspase Melanoma
Heterogeneity Bcl-2
Inhibitor Cell signaling
Kinase Proteins
Ligand Apoptosis
Melanoma Programmed cell death
Mimetics Cell biology
Mitochondria Branches of biology
Mortality Related tumor
Oxygen Cancers
Prime TRAIL melanoma
Protein Melanoma therapy
Receptor
Rheostat
ROS
Sensitization
Targeted Therapy
TNF
TRAIL
Tumor

Semantics

Type Source Name
gene UNIPROT BAX
gene UNIPROT ROS1
drug DRUGBANK Rosoxacin
gene UNIPROT XIAP
gene UNIPROT DIABLO
gene UNIPROT BCL2
pathway BSID Cell Cycle
pathway BSID Cell cycle
pathway BSID Apoptosis
gene UNIPROT TNF
disease MESH development
disease DOID cancer
disease MESH cancer
drug DRUGBANK Spinosad
pathway BSID Melanoma
disease DOID Melanoma
disease MESH Melanoma
gene UNIPROT TNFSF10

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