Resistance to BRAF inhibitors represents a significant clinical obstacle. Overcoming this challenge requires the development of appropriate models of resistance and studies aimed at elucidating mechanisms of resistance. Understanding these mechanisms is vital to developing rational drug combination strategies to prevent and/or treat resistance in these patients. Current mechanisms of vemurafenib resistance in BRAF V600E melanoma have been acquired from limited sampling of established cell lines and from patients that failed prior chemotherapy regimens. We are currently utilizing novel high throughput models of melanoma in order to identify and verify vemurafenib resistance mechanisms in vivo including our recently described mouse model of melanoma based on the RCAS-TVA system and the assessment of BRAF V600E melanoma tumor grafts derived from chemo-naïve patients.

Major advantages of the RCAS-TVA mouse model are the defined nature of the induced tumors (e.g., B-Raf, +/- Cdkn2a +/- Pten), an intact immune system, high throughput capacity, and the ability to validate potential mechanisms rapidly. Inclusion of patient derived melanoma samples grafted into immune deficient mice allows for the characterization of vemurafenib response and resistance kinetics which can then be compared with matched patient responses. Based on the mechanisms of resistance we identify, and those recently reported, we will utilize both models to evaluate combinatorial therapeutic strategies to counter vemurafenib resistance. The goal of these studies is to provide a significant advancement in the understanding of the mechanisms of resistance to BRAF inhibition in melanoma and that will translate into better patient stratification and therapeutic intervention strategies.