Repurposing an HIV drug to improve efficacy of targeted therapy in melanoma

Targeted mitogen-activated protein kinase inhibitor (MAPKi) therapies have had limited efficacy in patients with v-Raf murine sarcoma viral oncogene homolog B (BRAF) -mutant, unresectable or metastatic melanomas and tumor relapse is almost inevitable (1). There has been a great deal of studies dissecting heterogeneous molecular mechanisms of acquired resistance to mutant BRAF-targeted therapies. For example, up-regulation of mitochondrial biogenesis and altered tumor bioenergetics (2), increased phosphorylation of protein kinase B (AKT) (3), and selection for subpopulations expressing epidermal growth factor receptor (EGFR) (4) are mechanisms responsible for acquired resistance. Some approaches to overcome acquired drug resistance are combining MAPKi with immune checkpoint blockade inhibitor targeting programmed cell death protein 1 (PD-1) (5), targeting both the MAPK and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT pathway (6), and targeting mitochondrial biogenesis through inhibition of tumor necrosis factor receptor-associated protein 1 (TRAP1) (2). However, much work needs to be done in investigating and therapeutically preventing the emergence of the initial intrinsic resistance to MAPKi