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The emergence of RAS-driven secondary cancers and BRAF-inhibitor resistance has led to the development of combination therapies targeting both BRAF and MEK.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Aims<\/jats:title>\n            <jats:p>This study explored the mechanisms underlying the synergistic effects of dabrafenib (DAB) and trametinib (TM) in drug-resistant A375 and RPMI 7951 melanoma cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Cytotoxicity was assessed via MTT assay and combination effects were evaluated via combination index analysis. Apoptosis was analyzed by DNA fragmentation ELISA, while ectopic let-7a miRNA expression and inhibition were performed using lipofection. Gene expression levels were quantified by qRT-PCR, and protein expression was assessed via Western blot.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The combination of 0.7 \u03bcM DAB and 5.0 \u03bcM TM exhibited synergistic cytotoxicity by inhibiting the pERK1\/2 signaling pathway and inducing MITF expression. This resulted in mitochondria-mediated apoptosis, characterized by a decrease in anti-apoptotic Bcl-2 and an increase in pro-apoptotic Bax, caspase-9, and caspase-3 levels. Additionally, Let-7a was identified as a crucial regulator of apoptosis sensitivity by targeting caspase-3, the key executor of apoptosis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>These findings provide new insights into overcoming melanoma drug resistance through combined BRAF\/MEK inhibition.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s11845-025-03923-6","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T05:58:45Z","timestamp":1741586325000},"page":"797-805","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Let-7a microRNA modulates caspase-3-dependent apoptosis in melanoma cells treated with dabrafenib and trametinib combination"],"prefix":"10.1007","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3834-0863","authenticated-orcid":false,"given":"Murat","family":"Keser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8459-4373","authenticated-orcid":false,"given":"Harika","family":"Atmaca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,10]]},"reference":[{"key":"3923_CR1","doi-asserted-by":"publisher","unstructured":"Davis LE, Shalin SC, Tackett AJ (2019) Current state of melanoma diagnosis and treatment. 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