Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15–25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR _1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR _1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR _1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR _1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.

Cutaneous melanoma is one of the 5 most common cancers in the United States and is the most common fatal malignant neoplasm in young adults. Melanoma rates are consistently rising; in 2014, 76 100 individuals will be diagnosed with melanoma of the skin, and 9710 cases will result in death.¹ Several cohort studies have suggested a higher incidence of melanoma in pilots and flight crew.^2,3 Flight-based workers are thought to have a greater occupational hazard risk of melanoma owing to increased altitude-related exposure to UV and cosmic radiation. Although the risks of exposure to ionizing radiation for pilots and cabin crew are known and levels are regularly monitored, UV exposure is not a well-recognized occupational risk factor for the flight crew.

Immunotherapy is a cornerstone in the treatment of melanoma, and is intended to modulate the host immunity against the tumor. Immunotherapy can be used in an adjuvant setting, after complete surgical excision in patients with a high risk of disease relapse and as a treatment in advanced (unresectable or metastatic) stages. Development of novel therapeutic approaches and the optimization of existing therapies hold a great promise in the field of melanoma therapy research. Different clinical trials are ongoing, and immunotherapy is showing the ability to confirm durable clinical benefits in selected groups of melanoma patients. The aim of this review is to summarize different types of immunotherapy agents, as well as to discuss different strategies, complementary regimens, and possible biomarkers of response to the treatment.

Aptamer modified gold nanoparticles target malignant cells. Anti-cancer therapeutics are released after cleavage of a self-immolative linker by intracellular triggers.