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the high CISs found only in the PLX4720-resistant tumors. Further characterization revealed four transposon sites in the first intron of ERAS, with an integration pattern signifying gene activation. The PLX4720-resistance conferring phenotype was confirmed in human melanoma cell lines ectopically expressing ERas. Further mechanistic studies revealed that ERAS inactivation of BAD (BCL2-associated agonist of cell death) through the PI3K/AKT pathway contributed to the observed PLX4720 drug resistance. The authors characterize a novel melanoma resistance gene identified from a transposon-mediated in vivo mutagenesis screen in mechanistic details. Future studies of the other candidate resistance genes may reveal novel mechanisms independent of MAPK or PI3K pathways. Most importantly, comparing candidates to gene expression profiles of treatment na€ıve and resistant human primary tumor samples can be an added filter to identify biologically relevant genes. This report highlights the first example of the use of SB transposon-mediated mutagenesis in a murine melanoma model to identify genes that confer PLX4720 drug resistance. The authors also demonstrate a robust drug treatment regimen to evaluate drug efficacy in a GEM model that closely resembles the treatment course of melanoma patients. Future analysis of larger cohorts of tumors resistant to BRAF inhibition and/or other drug combinations may reveal more complex resistance mechanisms. In addition to identifying novel resistance mechanisms, the authors have demonstrated a powerful platform to test novel and more effective drug combinations in vivo to overcome PLX4720-mediated resistance.