Oxidative Stress-Related Mechanisms in Melanoma and in the Acquired Resistance to Targeted Therapies

Abstract

Melanoma is a highly aggressive cancer with the poorest prognosis, representing the deadliest form of skin cancer. Activating mutations in BRAF are the most frequent genetic alterations, present in approximately 50% of all melanoma cases. The use of specific inhibitors towards mutant BRAF variants and MEK, a downstream signaling target of BRAF in the MAPK pathway, has significantly improved progression-free and overall survival in advanced melanoma patients carrying BRAF mutations. Nevertheless, despite these improvements, resistance still develops within the first year of therapy in around 50% of patients, which is a significant problem in managing BRAF-mutated advanced melanoma. Understanding these mechanisms is one of the mainstreams of the research on BRAFi/MEKi acquired resistance. Both genetic and epigenetic mechanisms have been described. Moreover, in recent years, oxidative stress has emerged as another major force involved in all the phases of melanoma development, from initiation to progression until the onsets of the metastatic phenotype and chemoresistance, and has thus become a target for therapy. In the present review, we discuss the current knowledge on oxidative stress and its signaling in melanoma, as well as the oxidative stress-related mechanisms in the acquired resistance to targeted therapies.

Disruption of Redox Homeostasis by Alterations in Nitric Oxide Synthase Activity and Tetrahydrobiopterin along with Melanoma Progression

“…Superoxide anion acts for malignant transformation, and low concentrations of BH4 could favor tumorigenesis. On the other hand, it is known that high concentrations of ROS can lead to cell death; thus, tumor cells can increase the antioxidant system to protect and ensure tumor progression [ 50 , 51 , 77 ]. In advanced-stage melanoma, the increase in BH4 levels may be one of the mechanisms to keep the O 2 •− levels within the limit for the survival of these cells.…”

Ultrasound-Responsive Nrf2-Targeting siRNA-Loaded Nanobubbles for Enhancing the Treatment of Melanoma

“…Several genetic and epigenetic mechanisms have been described in MM resistance to therapeutical approaches [8,9]. However, in recent years, researchers have focused their attention on oxidative stress being able to play a central role in tumor progression [10], including melanoma [11]. Indeed, a growing body of evidence indicates that, compared with normal, healthy tissue, tumor tissues exhibit a high level of reactive oxygen species (ROS), which allow the activation of the pro-tumorigenic signaling pathway [10].…”

Upregulation of miR-34a-5p, miR-20a-3p and miR-29a-3p by Onconase in A375 Melanoma Cells Correlates with the Downregulation of Specific Onco-Proteins

“…Melanoma is an aggressive cancer associated with the poorest prognosis. Activating mutations in the BRAF gene are the most frequent genomic alterations, present in more than half of all melanoma cases [24]. Unfortunately, target therapy with BRAF-inhibitors or MEK-inhibitors does not exclude recurrence of the malignancy and the incoming of therapy resistance [24].…”

“…Activating mutations in the BRAF gene are the most frequent genomic alterations, present in more than half of all melanoma cases [24]. Unfortunately, target therapy with BRAF-inhibitors or MEK-inhibitors does not exclude recurrence of the malignancy and the incoming of therapy resistance [24]. Recently, we reported a significant anti-melanoma activity exerted by low micromolar ONC concentrations in both A375 and MeWo human malignant melanoma cell lines [12,17,25].…”