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.
Highlights
Melanoma is a highly aggressive cancer with the poorest prognosis, representing the deadliest form of skin cancer
The major source of ROS/RNS has been attributed to the dysfunction of mitochondrial respiratory chain enzymes [99]; in melanoma, other enzymes seem to play a major role in ROS production: the NOX family, nitric oxide synthases (NOSs), arachidonic acid cyclooxygenases (COXs), and lipoxygenases (LOXs) [76,94]
Cantharidin, a terpenoid isolated from the insect mylabris (Mylabris phalerata Pallas), and Withaferin A (WFA), a withanolide derived from the medicinal plant Withania somnifera, have demonstrated antitumorigenic activity in melanoma through the generation of ROS [140,141]
Summary
Melanoma, which originates from a malignant transformation of melanocytes, is the third most common malignant tumor of the skin, after the most frequent basal cell carcinoma and the squamous cell carcinoma, both of which arise from keratinocytes or their precursors. At 3-year analysis, the combination showed a median OS of 33.6 months, while vemurafenib alone showed a median OS of 16.9 months [17]; the median PFS was 14.9 months with the combination and 7.3 months with monotherapy Despite these improvements, after the combined treatment, nearly 50% of patients developed resistance within the first year of the targeted therapy, representing the most challenging management problem of the disease [12]. Other studies have demonstrated that during the acquisition of the resistance to targeted therapies, a population of melanoma cells exhibited low MITF expression [36] In addition to these molecular mechanisms, in recent years, researchers have focused their attention on oxidative stress as a major force in eliciting genetic mutations and controlling gene expression. We discuss the current knowledge on oxidative stress and its signaling in melanoma and the oxidative stress-related mechanisms in acquired resistance to targeted therapies
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