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Simple Summary Mutations in NRAS are the second most common driver mutation in melanoma and lack therapy options. We discovered that p38 plays the role of a tumor suppressor in NRAS mutant melanoma. In this study, we characterized the significance of short and long term p38 activation which can in turn modulate other pathways downstream. An important of effect of long term p38 activation is the phosphorylation of mTOR. As a result of mTOR phosphorylation, a suppression in autophagy and actin remodeling follows. Our candidate tumor suppressor p38 as well as its downstream targets such as phosphorylation of mTOR, actin remodeling and autophagy can be modulated with pharmacologically available small molecules such as anisomycin, rapamycin, hydroxychloroquine and cytochalasin. Further investigation to modulate a combination of these compounds along with FDA approved drugs like MEK inhibitors can be a novel strategy to treat NRAS mutant melanomas. Hotspot mutations in the NRAS gene are causative genetic events associated with the development of melanoma. Currently, there are no FDA-approved drugs directly targeting NRAS mutations. Previously, we showed that p38 acts as a tumor suppressor in vitro and in vivo with respect to NRAS-mutant melanoma. We observed that because of p38 activation through treatment with the protein synthesis inhibitor, anisomycin leads to a transient upregulation of several targets of the cAMP pathway, representing a stressed cancer cell state that is often observed by therapeutic doses of MAPK inhibitors in melanoma patients. Meanwhile, genetically induced p38 or its stable transduction leads to a distinct cellular transcriptional state. Contrary to previous work showing an association of invasiveness with high p38 levels in BRAF-mutated melanoma, there was no correlation of p38 expression with NRAS-mutant melanoma invasion, highlighting the difference in BRAF and NRAS-driven melanomas. Although the role of p38 has been reported to be that of both tumor suppressor and oncogene, we show here that p38 specifically plays the role of a tumor suppressor in NRAS-mutant melanoma. Both the transient and stable activation of p38 elicits phosphorylation of mTOR, reported to be a master switch in regulating autophagy. Indeed, we observed a correlation between elevated levels of phosphorylated mTOR and a reduction in LC3 conversion (LCII/LCI), indicative of suppressed autophagy. Furthermore, a reduction in actin intensity in p38-high cells strongly suggests a role of mTOR in regulating actin and a remodeling in the NRAS-mutant melanoma cells. Therefore, p38 plays a tumor suppressive role in NRAS-mutant melanomas at least partially through the mechanism of mTOR upregulation, suppressed autophagy, and reduced actin polymerization. One or more combinations of MEK inhibitors with either anisomycin, rapamycin, chloroquine/bafilomycin, and cytochalasin modulate p38 activation, mTOR phosphorylation, autophagy, and actin polymerization, respectively, and they may provide an alternate route to targeting NRAS-mutant melanoma.
