Combining Bioactive Cell-Penetrating Peptides and Vemurafenib to Produce Peptide–Drug Conjugates with Activity Against Drug-Resistant Melanoma Cells

Abstract

Acquired drug resistance remains a challenge for treating melanoma. Monotherapies such as vemurafenib and dabrafenib, which target a mutant form of BRAF kinase, become ineffective within six months of treatment. Therapies that combine multiple drugs targeting the same cellular pathway have emerged as a strategy to reduce drug resistance development. To determine whether additional benefits could be achieved by combining anticancer compounds with distinct killing mechanisms, we synthesized a suite of peptide–drug conjugates (PDCs) containing vemurafenib and peptides with either membrane-disruptive anticancer activity or nondisruptive properties. The PDCs crossed membranes with the drug cargo attached and killed melanoma cells with similar or improved activity relative to the free drug. The choice of peptide carrier impacted overall PDC potency and selectivity, and we identified an optimal membrane-active carrier peptide where the Vem-containing PDC exhibited activity against both drug-naı̈ve and drug-resistant melanoma cells while maintaining selectivity over noncancer cells. Show more