Pterostilbene enhances dabrafenib activity in BRAF mutant melanoma through synergistic MAPK suppression and apoptotic induction

Resistance to BRAF inhibitors limits durable responses in melanoma. Pterostilbene (PTB), a dietary polyphenol, has anti-proliferative and pro-apoptotic properties and may augment targeted therapy. We evaluated whether PTB enhances the activity of the BRAF inhibitor dabrafenib (DAB) in BRAF-mutant melanoma cells. IC₅₀ values for PTB and DAB were determined in A375 and HT144 melanoma cells following 48 h treatment. Synergy studies were conducted in HT144 cells using 5×5 fixed-ratio matrices based on experimentally determined IC₅₀ values, and synergy was quantified using Loewe additivity, Bliss independence, ZIP synergy, and Combination Index models. Mechanistic effects were assessed by Western blot analysis of key markers of MAPK signaling and apoptosis. In A375 cells, IC₅₀ values were ~12 nM for DAB and ~60 μM for PTB. In HT144 cells, IC₅₀ values were ~3 nM for DAB and ~45 μM for PTB. Multiple PTB+DAB combinations in HT144 produced strong synergy, with the most synergistic doses (e.g., PTB ~12 μM + DAB ~0.8-3 nM) showing Loewe CI < 0.7 and corresponding Bliss/ZIP synergy. Synergistic treatment decreased MAPK pathway activation and increased apoptotic markers relative to single agents, consistent with enhanced signaling suppression and apoptosis induction. PTB enhances DAB efficacy in BRAF-mutant HT144 melanoma cells, producing robust synergy and mechanistic evidence of MAPK pathway inhibition and apoptosis. These findings support further evaluation of PTB as a low-toxicity adjuvant to improve responses to BRAF-targeted therapy in melanoma.