Extracellular Vesicles in Cancer Drug Resistance: Implications on Melanoma Therapy

Simple Summary Melanoma represents only 1% of human skin cancers, but in several cases can lead to the death of the patient. Nowadays, there are different systemic therapies used for the treatment of human melanoma. Although these substantially improve patients' lifespan, they are still associated with resistance. Extracellular vesicles (EVs), tiny vesicles released by tumor cells involved in intercellular communication, play an important role in melanoma pathogenesis and progression. They are crucially involved in several mechanisms of cancer drug resistance in several types of cancer, and there is a strong indication that EVs released by melanoma cells might play a role in the development of resistance, modulating the response towards anti-cancer drugs. Understanding their role will help improve the outcome of melanoma treatment. Extracellular vesicles (EVs) are involved in the pathogenesis of neoplastic diseases. Their role in mediating drug resistance has been widely described in several types of cancers, including melanoma. EVs can mediate drug resistance through several different mechanisms, such as drug-sequestration, transfer of pro-survival proteins and RNA, induction of cancer stem cell-like features and interaction with cells of the tumor microenvironment and immune-system. Melanoma is a highly immunogenic tumor originating from the malignant transformation of melanocytes. Several therapeutic strategies currently used in the treatment of melanoma and the combination of BRAF and MEK-inhibitors, as well as immune check-point inhibitors (ICI), have consistently improved the overall survival time of melanoma patients. However, the development of resistance is one of the biggest problems leading to a poor clinical outcome, and EVs can contribute to this. EVs isolated from melanoma cells can contain "sequestered" chemotherapeutic drugs in order to eliminate them, or bioactive molecules (such as miRNA or proteins) that have been proven to play a crucial role in the transmission of resistance to sensitive neoplastic cells. This leads to the hypothesis that EVs could be considered as resistance-mediators in sensitive melanoma cells. These findings are a pivotal starting point for further investigations to better understand EVs' role in drug resistance mechanisms and how to target them. The purpose of this review is to summarize knowledge about EVs in order to develop a deeper understanding of their underlying mechanisms. This could lead to the development of new therapeutic strategies able to bypass EV-mediated drug-resistance in melanoma, such as by the use of combination therapy, including EV release inhibitors.