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The progression of these tumors involves metabolic adaptations, which also affect the cellular redox status. Previous studies have linked RAF kinase signaling, a key component of the MAPK\/ERK pathway involved in cell division and survival, to the suppression of mitochondrial reactive oxygen species (ROS) production, resulting in protection against cell death. In BRAF\u2010transformed cells, we have identified impaired JNK1\/2\u2010dependent activation of the mitochondrial prooxidant protein p66Shc as a potential cause. In the present study, we dissected signaling and mitochondrial alterations that characterize the transition from BRAFi responsiveness to resistance in A375 melanoma cells. Insensitivity to BRAFi dabrafenib exposure was associated with reactivation of ERK1\/2 phosphorylation, increased JNK1\/2 kinase activity, p66ShcS36 phosphorylation, and elevated ROS production. Utilizing high\u2010resolution respirometry (HRR) and transmission electron microscopy (TEM), we show that dabrafenib\u2010resistant cells displayed mitochondrial damage, compensated by increased respiration, leading to high ROS levels. Moreover, dabrafenib\u2010resistant cells (A375D) have more efficient antioxidant systems, which may explain why despite ongoing cell death, net cell growth was observed. Treatment of both parental and resistant cells with phenethyl isothiocyanate (PEITC) increased ROS production but caused substantial cell death only in A375D melanoma cells. This PEITC effect could be demonstrated in two further dabrafenib\u2010resistant cell lines, WM164D and 451LuP. These results suggest that the altered redox status is linked to compromised mitochondria and is associated with the development of BRAFi resistance, rendering cells exquisitely sensitive to the actions of selective ROS\u2010inducing therapeutics.<\/jats:p>","DOI":"10.1002\/1878-0261.70169","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T06:32:26Z","timestamp":1764743546000},"page":"1202-1219","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploiting metabolic adaptations to overcome dabrafenib treatment resistance in melanoma cells"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9778-6489","authenticated-orcid":false,"given":"Silvia","family":"Eller","sequence":"first","affiliation":[{"name":"Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery Medical University of Innsbruck  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