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Simple Summary  The management of unresectable and metastatic cutaneous melanoma has substantially improved with the introduction of molecular targeted therapy (BRAF and MEK inhibitors) and immunotherapy (Immune checkpoint inhibitors). The avenue of precision oncology holds promise in melanomas due to the high rate of somatic mutations that contribute to tumor progression. In this review article, we discuss common mutations and altered pathways that are implicated in melanomagenesis including oncogenic driver mutations, tumor suppressor gene alterations, fusion oncogenes, epigenetic regulators and alterations in the DNA-damage response pathway. We also provide a comprehensive review of promising individualized novel treatment approaches in non-BRAF mutant melanoma.    Abstract  Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. High-resolution and high-throughput technology has led to the identification of distinct mutational signatures and their downstream alterations in several key pathways that contribute to melanomagenesis. This has enabled the development of individualized treatments by targeting specific molecular alterations that are vital for cancer cell survival, which has resulted in improved outcomes in several cancers, including melanomas. To date,  BRAF  and  MEK  inhibitors remain the only approved targeted therapy with a high level of evidence in  BRAF V600E/K   mutant melanomas. The lack of approved precision drugs in melanomas, relative to other cancers, despite harboring one of the highest rates of somatic mutations, advocates for further research to unveil effective therapeutics. In this review, we will discuss potential druggable mutations and the ongoing research of novel individualized treatment approaches targeting non- BRAF  mutations in melanomas.

Melanoma Targeted Therapies beyond BRAF-Mutant Melanoma: Potential Druggable Mutations and Novel Treatment Approaches