Repurposing a Clinical Antimalarial for the Therapeutic Induction of Lethal ER Stress Targeting BRAF-Kinase Inhibitor-Resistant Malignant Melanoma

The document reports on the repurposing of mefloquine (MQ), a clinical antimalarial drug, for the treatment of BRAF-kinase inhibitor-resistant malignant melanoma. The study found that MQ effectively induces lethal endoplasmic reticulum (ER) stress in both vemurafenib-resistant (A375R) and vemurafenib-sensitive (A375) melanoma cells at low micromolar concentrations. The research demonstrated that A375R cells were more sensitive to MQ-induced apoptotic elimination. Gene expression analysis showed that MQ triggers both ER and redox stress responses before cell viability loss. Additionally, the study observed ER swelling, cytosolic calcium overload, and initiation of the mitochondrial cell death pathway in treated cells. In a murine A375 melanoma xenograft model, MQ showed single-agent activity, suggesting its potential as a repurposed drug for chemotherapeutic elimination of malignant melanoma cells.