Abstract
Advances in the use of targeted and immune therapies have revolutionized the clinical management of melanoma patients, prolonging significantly their overall and progression-free survival. However, both targeted and immune therapies suffer limitations due to genetic mutations and epigenetic modifications, which determine a great heterogeneity and phenotypic plasticity of melanoma cells. Acquired resistance of melanoma patients to inhibitors of BRAF (BRAFi) and MEK (MEKi), which block the mitogen-activated protein kinase (MAPK) pathway, limits their prolonged use. On the other hand, immune checkpoint inhibitors improve the outcomes of patients in only a subset of them and the molecular mechanisms underlying lack of responses are under investigation. There is growing evidence that altered expression levels of microRNAs (miRNA)s induce drug-resistance in tumor cells and that restoring normal expression of dysregulated miRNAs may re-establish drug sensitivity. However, the relationship between specific miRNA signatures and acquired resistance of melanoma to MAPK and immune checkpoint inhibitors is still limited and not fully elucidated. In this review, we provide an updated overview of how miRNAs induce resistance or restore melanoma cell sensitivity to mitogen-activated protein kinase inhibitors (MAPKi) as well as on the relationship existing between miRNAs and immune evasion by melanoma cell resistant to MAPKi.
Highlights
Melanoma represents one of the most aggressive skin cancers with a significantly increased incidence in the last decades [1,2,3]
The new immune checkpoint blockade therapies improve the outcomes of patients with advanced melanoma regardless of the mutation status and several ongoing clinical trials highlight that combinations of BRAF inhibitors (BRAFi) and MEK inhibitor (MEKi) with immune checkpoint inhibitors result in more durable responses in about 50% of patients [15,16,17]
It is currently accepted that distinct profiles of miRNA expression are detected at each step of melanoma development, and that an altered expression of miRNAs frequently correlates with poor prognosis and/or inadequate response to treatments
Summary
Melanoma represents one of the most aggressive skin cancers with a significantly increased incidence in the last decades [1,2,3]. Liu and co-workers showed that miR-200c is a potential therapeutic target to restore melanoma cell sensitivity to BRAFi. They found that miR-200c reverts drug resistance to PLX4720 BRAF and U0126 MEK inhibitors by down-regulating the p16 transcriptional repressor BMI-1, which, in turn, inhibits melanoma cell growth and metastases in nude mice. MiR-7 could inhibit the activation of the MAPK and PI3K/AKT pathways and reverse melanoma cell resistance to BRAFi, by decreasing the expression levels of EGFR and IGF-1R.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
