ABSTRACT The cardinal aberrant hallmarks of melanoma, the most lethal form of skin cancer, are driven by recurrent alterations in tumor suppressors and oncogenes, of which mutational activation of BRAF or NRAS is particularly common. Moreover, although therapeutic options for melanoma patients have been transformed by the advent of both immune-oncology (I/O) and pathway-targeted therapies, significant challenges remain in the treatment of this disease. For BRAF-driven melanoma patients who fail I/O therapy, their disease is often sensitive to FDA-approved pathway-targeted drugs that inhibit BRAFV600E signaling. By contrast, for patients with NRAS-driven melanoma, who are either ineligible for, or refractory to I/O therapy, their second-line options are limited and of limited therapeutic efficacy. Indeed, despite our detailed knowledge of key signaling pathways downstream of NRAS oncoproteins, there are no FDA- approved pathway-targeted therapies for the second-line treatment of NRAS-driven melanoma patients. Against this background, and to tackle these challenges, the long-term, overarching goal of our research is to design new combinations of pathway-targeted therapy for NRAS-driven melanoma that: 1. Increase the overall response rate and depth of each patient's primary anti-tumor response; 2. Maximize safety and tolerability, while minimizing toxicity and; 3. Enhance durability of response by forestalling the onset of lethal drug resistance. To that end, based on compelling preliminary data, the short-term aims of this R01 are: 1. Test the anti-melanoma activity of a novel, first-in-class direct pharmacological inhibitor of NRAS oncoprotein signaling; 2. Define mechanism(s) of resistance to such novel agents and; 3. Determine the role of autophagy as an adaptive mechanism of resistance to inhibition of NRAS oncoprotein signaling. To prosecute these aims we will leverage state-of-the-art resources including: 1. Innovative genetically engineered and melanoma patient-derived xenograft mouse models; 2. Companion NRAS- or BRAF-driven melanoma cell lines reflecting the full complexity of the disease; 3. An array of potent, specific and selective inhibitors of key melanoma signaling pathways with an emphasis on NRAS, RAF or PI3’-kinase signaling. In addition, an outstanding group of collaborators will provide support to critically evaluate the design, execution and results of the proposed research with a view to translating this research into investigator-initiated clinical trials to substantially improve the prognosis for patients with NRAS-driven melanoma. The overall and long-term impact of this research will lie in providing the mechanistic groundwork and scientific rationale for direct pharmacological targeting of NRAS oncoproteins, either as single agents or in therapeutic combinations, leading to new regimens of therapy thereby ultimately transforming NRAS-driven melanoma into a chronic or a curable disease.