SGK1 may represent a therapeutic target in BRAF-mutant melanoma

Despite advancements in treatment, the five-year survival rate for Stage IV melanoma remains low, around 30%, highlighting the urgent need for new therapies. Two key signaling pathways, RAS>RAF>MEK>ERK (MAPK) and PI3K>AKT, are often co-activated in melanoma and play a central role in its initiation and progression. About 50% of melanomas have a BRAF mutation, but many patients develop resistance to therapies targeting this pathway. Additionally, disruptions in the PI3K>AKT pathway, such as loss of the tumor suppressor PTEN or activation of PI3K or AKT, are common in BRAF-mutant melanomas. Despite promising preclinical studies, no PI3K or AKT inhibitors have been approved for advanced melanoma treatment. The serine/threonine kinase SGK1 (serum and glucocorticoid-regulated kinase 1) plays a pivotal role in cellular processes such as survival, proliferation, and migration, and has been implicated in various cancers, including melanoma. Our previous work has shown that AKT was inhibited, SGK1 was upregulated, potentially rescuing cell survival and acting as an inherent resistance mechanism for AKT inhibition. SGK1 was also found to be higher in primary melanoma tumors compared to normal skin lesions. In vivo experiments in a mouse melanoma model demonstrate that overexpressing SGK1 promotes tumor growth and reduces survival, and these experiments are currently ongoing to examine the impact on metastasis in this mice. These findings position SGK1 as a promising therapeutic target for melanoma, particularly in combination with existing treatment strategies. This body of work underscores the importance of further investigating SGK1's molecular mechanisms and its potential to improve melanoma treatment outcomes.