Melanoma is the third most common type of skin cancer, characterized by its heterogeneity and propensity to metastasize to distant organs. Melanoma is a heterogeneous tumor, composed of genetically divergent subpopulations, including a small fraction of melanoma-initiating cancer stem-like cells (CSCs) and many non-cancer stem cells (non-CSCs). CSCs are characterized by their unique surface proteins associated with aberrant signaling pathways with a causal or consequential relationship with tumor progression, drug resistance, and recurrence. Melanomas also harbor significant alterations in functional genes (BRAF, CDKN2A, NRAS, TP53, and NF1). Of these, the most common are the BRAF and NRAS oncogenes, with 50% of melanomas demonstrating the BRAF mutation (BRAF^V600E). While the successful targeting of BRAF^V600E does improve overall survival, the long-term efficacy of available therapeutic options is limited due to adverse side effects and reduced clinical efficacy. Additionally, drug resistance develops rapidly via mechanisms involving fast feedback re-activation of MAPK signaling pathways. This article updates information relevant to the mechanisms of melanoma progression and resistance and particularly the mechanistic role of CSCs in melanoma progression, drug resistance, and recurrence.

A 56-year-old woman with a 40-year history of guttate flares of psoriasis associated with stress and infection as well as chronic asthma was treated with subcutaneous injections of ustekinumab, repeated after 1 month and then every 3 months. Her psoriasis completely resolved, and her capacity for exercise was markedly increased and asthma maintenance medications were no longer needed. Ustekinumab is a human monoclonal antibody that binds the p40 subunit of IL-12 and IL-23 to limit the progression of the Th1 and Th17 inflammatory immune responses that maintain many autoimmune and inflammatory diseases. Th17-related responses drive inflammation during late stages of chronic asthma and can also be blocked by ustekinumab. Blocking the underlying cytokine-mediated inflammatory responses for psoriasis with ustekinumab can also treat other chronic inflammatory diseases.