Dihydrotanshinone I in Paired Vemurafenib-Sensitive and Resistant A375 Melanoma Cells

Acquired resistance limits the response of melanoma to vemurafenib. This study investigated dihydrotanshinone I (DHT) in parental A375 cells and a vemurafenib-resistant derivative (A375R). An exploratory computational workflow combined target prediction, survival associations, tumor-versus-normal expression comparisons, dependency screening, least absolute shrinkage and selection operator (LASSO) Cox regression, and random survival forests. Heat shock protein 90 alpha family class A member 1 (HSP90AA1) and signal transducer and activator of transcription 3 (STAT3) were prioritized for cellular testing. Cellular thermal shift assays showed DHT-associated thermal stabilization, and combined small interfering RNA depletion produced greater phenotypic effects than single-target depletion. Eight drug combinations yielded Chou–Talalay combination indices of 0.520–0.940 in A375R cells. Transcriptional changes and lipid-peroxidation readouts were consistent with altered resistance-associated and oxidative-stress programs. Together, these findings support further investigation of HSP90AA1 and STAT3 in the response of resistant melanoma cells to DHT.