Abstract B10: Overcoming resistance to B-Raf targeting agents using LPD nanotechnology

Constitutively active mutant V600EB-RAF is present in 50% to 60% of sporadic melanomas and vemurafenib is a selective inactivating inhibitory drug. While the compound is initially effective in 80% patients, most of the patients eventually developed more invasive resistant disease. Unraveling the mechanisms leading to the development of vemurafenib resistance is key to developing better treatment strategies that can overcome the process and provide patients with more effective treatment options. Here we show that vemurafenib inhibits ERK activity to negatively regulate tumor suppressor Sprouty4 expression to increase Akt3 activity, leading to the development of drug-resistant melanomas. Combining vemurafenib with sigma receptor targeted LPD nanoparticle technology containing Akt3 siRNA and suppressor Sprouty4 plasmid simultaneously inhibit MAPK and Akt3, preventing resistant tumor development in xenografted mice. Our studies have identified a novel mechanism leading to the development of resistant melanoma following vemurafenib treatment and development of a novel melanoma cell targeting nanotechnology-based therapeutic agent for combating the development of resistance.