Chemoresistance in cutaneous melanoma: contemporary and future aspects

Melanoma is one of the most common types of skin cancer and is the most lethal type of skin cancer presently. Despite the presence of various drugs for the treatment of melanomas, increasing resistance to the existing treatment is a major concern. Due to the involvement of complex mechanisms including genetic mutations, the presence of neoantigens, tumor microenvironment, and cellular plasticity, the tumor cell develops the ability to evade the effects of current therapies including targeted drugs and immunotherapy limiting the treatment efficacy. This leads to difficulties in achieving long-term control in patients with advanced melanoma. It is important to understand the molecular mechanisms underlying chemoresistance to overcome this resistance and develop potential therapeutic strategies. In this article, we will discuss the most common drugs used to fight skin cancer and their mechanisms of fighting cancer, followed by a discussion of intrinsic resistance and extrinsic resistance. We will address molecular mechanisms of chemoresistance including the alteration in apoptosis and lipid metabolism, the role of tumor microenvironments, genetic and epigenetic mutations, phenotypic switching of cells, and the presence of neoantigens. Next, the strategies to overcome drug resistance including blocking alternative pathways that cancer cells use to avoid treatment, using combination therapies that target multiple signaling pathways, and personalizing treatment regimens to account for a patient's genetic and immunologic characteristics have been discussed. Lastly, the need for advanced techniques including transcriptomic, metabolomics, and proteomics in identifying novel targets and therapies to treat hard-to-treat melanoma or skin cancers has been discussed.