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It inhibits the MAPK (mitogen-activated protein kinase)\/ERK (extracellular signal-regulated kinase) pathway and tumor proliferation in BRAFV600E-mutated melanoma cells. Resistance to vemurafenib has been reported in melanoma patients due to secondary NRAS (neuroblastoma RAS viral oncogene homolog) mutations, which lead to paradoxical MAPK pathway activation and tumor proliferation. However, the impact of this paradoxical activation on mitochondrial dynamics and function in NRAS-mutated melanoma is unclear. Here, we investigated the effects of vemurafenib on NRASQ61R-mutated melanoma cells, focusing on mitochondrial dynamics and function. As expected, vemurafenib did not exhibit cytotoxicity in SK-MEL-147 NRASQ61R-mutated melanoma cells, even after 72 h of incubation. However, it significantly enhanced the MAPK\/ERK signaling through paradoxical activation, accompanied by decreased expression of mitochondrial fusion proteins and activation of the fission protein DRP1 (dynamin-related protein 1), leading to small, rounded mitochondrial morphology. These observations were corroborated by transcriptome data obtained from NRAS-mutated melanoma patients, showing MFN1 (mitofusin 1) and OPA1 (optic atrophy 1) downregulation and DNM1L (DRP1 gene) upregulation. Interestingly, inhibition of mitochondrial fission with mdivi-1 or modulation of oxidative phosphorylation via respiratory chain inhibition or uncoupling significantly sensitized NRASQ61R-mutated melanoma cells to vemurafenib. Despite vemurafenib\u2019s low cytotoxicity in NRAS-mutated melanoma, targeting mitochondrial dynamics and\/or oxidative phosphorylation may offer a promising strategy for combined therapy.<\/jats:p>","DOI":"10.3390\/ijms26062675","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T06:36:23Z","timestamp":1742193383000},"page":"2675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Exploiting Paradoxical Activation of Oncogenic MAPK Signaling by Targeting Mitochondria to Sensitize NRAS Mutant-Melanoma to Vemurafenib"],"prefix":"10.3390","volume":"26","author":[{"given":"Laura Francisca Leite do","family":"Prado-Souza","sequence":"first","affiliation":[{"name":"Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo Andre, Sao Paulo 09210-580, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7915-0081","authenticated-orcid":false,"given":"Let\u00edcia Silva","family":"Ferraz","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo Andre, Sao Paulo 09210-580, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4678-8935","authenticated-orcid":false,"suffix":"Jr.","given":"Tharc\u00edsio","family":"Citrangulo Tortelli","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Oncology (LIM24), Cancer Institute of the State of Sao Paulo (ICESP), Clinical Hospital of the University of Sao Paulo Medical School (HCFMUSP), Sao Paulo 01246-000, Brazil"},{"name":"Comprehensive Center for Precision Oncology, University of S\u00e3o Paulo, Sao Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4604-9945","authenticated-orcid":false,"given":"C\u00e9sar Augusto Jo\u00e3o","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo Andre, Sao Paulo 09210-580, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danilo Trabuco do","family":"Amaral","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo Andre, Sao Paulo 09210-580, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise Costa","family":"Arruda","sequence":"additional","affiliation":[{"name":"Integrated Biotechnology Nucleus (NIB), University of Mogi das Cruzes (UMC), Mogi das Cruzes, Sao Paulo 08780-911, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1624-4021","authenticated-orcid":false,"given":"\u00c9rica Aparecida de","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0342-8726","authenticated-orcid":false,"given":"Roger","family":"Chammas","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Oncology (LIM24), Cancer Institute of the State of Sao Paulo (ICESP), Clinical Hospital of the University of Sao Paulo Medical School (HCFMUSP), Sao Paulo 01246-000, Brazil"},{"name":"Comprehensive Center for Precision Oncology, University of S\u00e3o Paulo, Sao Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4771-6041","authenticated-orcid":false,"given":"Silvya Stuchi","family":"Maria-Engler","sequence":"additional","affiliation":[{"name":"Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1277-0224","authenticated-orcid":false,"given":"Tiago","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo Andre, Sao Paulo 09210-580, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chaiprasongsuk, A., and Panich, U. 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