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

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.