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We used transgenic zebrafish to model NRAS\u2010mutant melanoma, and the rapid tumor onset allowed us to study candidate tumor suppressors. We identified P38\u03b1\u2010MAPK14 as a potential tumor suppressor in The Cancer Genome Atlas melanoma cohort of NRAS\u2010mutant melanomas, and overexpression significantly increased the time to tumor onset in transgenic zebrafish with NRAS\u2010driven melanoma. Pharmacological activation of P38\u03b1\u2010MAPK14 using anisomycin reduced in vitro viability of melanoma cultures, which we confirmed by stable overexpression of p38\u03b1. We observed that the viability of MEK inhibitor resistant melanoma cells could be reduced by combined treatment of anisomycin and MEK inhibition. Our study demonstrates that activating the p38\u03b1\u2010MAPK14 pathway in the presence of oncogenic NRAS abrogates melanoma in vitro and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The significance of our study is in the accountability of NRAS mutations in melanoma. We demonstrate here that activation of p38\u03b1\u2010MAPK14 pathway can abrogate NRAS\u2010mutant melanoma which is contrary to the previously published role of p38\u03b1\u2010MAPK14 pathway in BRAF mutant melanoma. These results implicate that BRAF and NRAS\u2010mutant melanoma may not be identical biologically. We also demonstrate the translational benefit of our study by using a small molecule compound\u2010anisomycin (already in use for other diseases in clinical trials) to activate p38\u03b1\u2010MAPK14 pathway.<\/jats:p><\/jats:sec>","DOI":"10.1111\/pcmr.12925","type":"journal-article","created":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T07:46:30Z","timestamp":1600328790000},"page":"150-162","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["NRAS<sup>Q61K<\/sup> melanoma tumor formation is reduced by p38\u2010MAPK14 activation in zebrafish models and NRAS\u2010mutated human melanoma cells"],"prefix":"10.1111","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7013-1132","authenticated-orcid":false,"given":"Ishani","family":"Banik","sequence":"first","affiliation":[{"name":"University Hospital Zurich University of Zurich Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phil F.","family":"Cheng","sequence":"additional","affiliation":[{"name":"University Hospital Zurich University of Zurich Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M.","family":"Dooley","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute Hinxton, Cambridge UK"},{"name":"Max Planck Institute for Developmental Biology T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Travnickova","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit and Cancer Research UK Edinburgh Centre MRC Institute of Genetics and Molecular Medicine University of Edinburgh Western General Hospital Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Munise","family":"Merteroglu","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute Hinxton, Cambridge UK"},{"name":"Cambridge Institute of Therapeutic Immunology &amp; Infectious Disease (CITIID) Department of Medicine University of Cambridge Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinhard","family":"Dummer","sequence":"additional","affiliation":[{"name":"University Hospital Zurich University of Zurich Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth E.","family":"Patton","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit and Cancer Research UK Edinburgh Centre MRC Institute of Genetics and Molecular Medicine University of Edinburgh Western General Hospital Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth M.","family":"Busch\u2010Nentwich","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute Hinxton, Cambridge UK"},{"name":"Cambridge Institute of Therapeutic Immunology &amp; Infectious Disease (CITIID) Department of Medicine University of Cambridge Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5902-9420","authenticated-orcid":false,"given":"Mitchell P.","family":"Levesque","sequence":"additional","affiliation":[{"name":"University Hospital Zurich University of Zurich Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,9,24]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.044"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI79743"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0248-4900(01)01124-8"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/1758834017708160"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.5.8.2685"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1107303"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18020274"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09806"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1089\/zeb.2008.0544"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(95)00357-F"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2007.03.010"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature00766"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-06-0711"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.12.013"},{"issue":"2","key":"e_1_2_7_16_1","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1101\/gad.14.2.158","article-title":"Direct regulation of nacre, a zebrafish MITF homolog required for pigment cell formation, by the Wnt pathway","volume":"14","author":"Dorsky R. 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