Countering TRAIL Resistance in Melanoma

Abstract

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.

Mcl‐1 targeting strategies unlock the proapoptotic potential of TRAIL in melanoma cells

“…Apoptosis resistance represents a critical hallmark in cancer, 4 and the targeting of apoptosis pathways, for example, by the death ligand TRAIL, appears as a promising antitumor strategy. 18 The particular advantage of TRAIL is based on its capability to selectively induce apoptosis in cancer cells, while normal cells are largely spared. 13,14 TRAIL agonists have proven good tolerability and safety profiles in clinical trials, however, an additional clinical benefit, when TRAIL was applied in combination therapies, so far remained on a low level.…”

“…In this context, the control of mitochondrial apoptosis pathways came into particular focus for explaining TRAIL resistance in melanoma. 17,18 Mitochondrial apoptosis pathways are decisively controlled by the family of Bcl-2 proteins, which share one to four distinct Bcl-2 homology (BH) domains. Bcl-2 proteins interact and control each other by heterodimerization.…”

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

“…The MDR phenotype of breast cancer cells was associated with abnormal activation of the PI3K/AKT/NF-κB signaling pathway 67 . Constitutive and inducible activation of PI3K/AKT/NF-κB in cancer cells (such as pancreatic cancer) are closely related to tumorigenesis and promoted MDR-like cell proliferation and apoptosis 68 . Ni et al reported that MDR of nasopharyngeal carcinoma (NPC) was reversed by inhibition of the PI3K/AKT/NF-κB signaling pathway.…”

Long non‑coding RNA regulation of TRAIL in breast cancer: A tangle of non‑coding threads (Review)

“…Cancer cells manage to grow and survive after hijacking TRAIL-mediated apoptosis ( 116 ). Tumor cells use Fas receptor as a reserve route to initiate activation of caspase 8 via proteolytic cleavage and hence induce apoptosis ( 117 , 118 ). In breast cancer, the expression levels of Fas and FasL are also downregulated, eliminating all apoptotic threats for cancerous cells and making their proliferation possible ( 119 ).…”