Background <p>Malignant melanoma is an aggressive tumor with high resistance to therapy. The emergence of RAS-driven secondary cancers and BRAF-inhibitor resistance has led to the development of combination therapies targeting both BRAF and MEK.</p> Aims <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.</p> Methods <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.</p> Results <p>The combination of 0.7 μM DAB and 5.0 μM 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.</p> Conclusions <p>These findings provide new insights into overcoming melanoma drug resistance through combined BRAF/MEK inhibition.</p> Graphical abstract <p></p>