(166g) Enhanced Response to Non-V600E BRAF Mutations in Melanoma By Self-Assembled Nanovector Assisted Drug Delivery

BRAF somatic missense mutations are highly frequent in malignant melanomas and, at lower frequency, in a wide range of human cancers. The majority of such mutations locate in the kinase domain, with a single substitution (V600E) accounting for 80% of cases. In our cohort of 1000 melanoma patients, besides the expected wild type and V600E/K carriers, we identified a group of patients harboring non-V600E mutations, including L597S/Q, A598V, T599Dup, and K601E. Our combined computational/experimental results showed remarkable differential in vitro responses of these BRAF mutant isoforms to a range of clinically approved BRAF inhibitors (Dabrafenib, Vemurafenib, Encorafenib) and other investigations drugs (AZ628, PLX8394), with BRAF A598V showing a remarkable positive response to all drug tested.

However, poor drug solubility/bioavailability and general toxicity constitute general challenging hurdles for cancer targeted therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for safer and more efficient cancer treatment. In this work, we present the characterization and the results obtained with our original nanomicellar drug delivery system based on an amphiphilic dendron, which could generate supramolecular micelles to effectively encapsulate the different BRAF inhibitors with high drug-loading capacity. The resulting drug-loaded nanomicelles were able to enhance drug potency in different cell models by significantly enhancing cellular uptake. In addition, the drug-loaded nanoparticles decreased significantly the toxicity related to the free drug.