Protein S-palmitoylation is a reversible post-translational modification that is present on proteins involved in numerous cellular processes including protein trafficking, lipid raft association, and protein complex formation. S-palmitoylation plays a significant role in the signal transduction pathway of the oncogenic NRAS protein, which is mutated in many cancers such as metastatic melanomas and hematopoietic tumors. This post-translational modification allows NRAS to traffic from the Golgi to the plasma membrane, thus enabling its downstream signaling cascade. Mutations in NRAS lead to an overactive protein that turns on downstream proteins involved in the cell growth and survival pathways, which contribute to cancer. About 15–25% of all metastatic melanoma patients harbor activating NRAS mutations; however, there are no currently approved targeted therapies for NRAS-mutated melanomas. Directly targeting the palmitoylation modification of NRAS can be a novel approach used to inhibit NRAS oncogenic activity by preventing association with the plasma membrane using compounds capable of cleaving endogenous S-palmitoyl modifications. Our group has synthesized a class of molecules capable of chemoselective reactions with long chain thioesters, which result in the efficient release of a free thiol. Specifically, live-cell imaging is utilized to study the molecular changes in NRAS localization when disrupted by the depalmitoylating agents. In addition, methods such as western blotting and cell viability assays are used to understand how targeting NRAS protein S-palmitoylation can contribute to changes in downstream signaling pathways in the context of NRAS-mutated melanoma <i>in vitro </i>and <i>in vivo</i>. These selective and reversible chemical agents for depalmitoylation could potentially serve as new drug candidates able to intercept and shut down cancer signaling through a novel mechanism, specifically for the treatment of NRAS-mutated melanoma.

Direct depalmitoylation of NRAS as a therapeutic strategy

2019 Fall National Meeting

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