Multi-omics analysis delineates resistance mechanisms associated with BRAF inhibition in melanoma

We generated drug resistant derivatives of four melanoma cell lines by subjecting them to selection pressure under targeted kinase inhibitors- Vemurafenib and Dabrafenib, and carried out genomic, proteomic and phosphoproteomic characterization of drug resistant clones and parental sensitive clones to delineate mechanisms of resistance. Multi-omics analysis carried out in this study enabled us to delineate both genetic and non-genetic resistance mechanisms to BRAF inhibitors. We delineated various resistance mechanisms to BRAFi and propose potential therapeutic targets to overcome BRAFi resistance. This study is a proof of principle to demonstrate that resistant clones generated in vitro recapitulate most resistance mechanisms observed in tumors. This is a useful approach to delineate potential resistance mechanisms that may emerge for novel targeted therapeutic agents even before they are administered in cancer patients. It enables anticipation of resistance mechanisms and potential second line treatment strategies that might offer durable response.