BRAF mutations are frequent in cutaneous melanomas and BRAF inhibitors(BRAFi) have shown remarkable clinical efficacy in BRAF mutant melanoma patients.,However, acquired drug resistance can occur rapidly and tumor(s) often progress thereafter.,Various mechanisms of BRAFi resistance have recently been described; however, the mechanism of resistance remains controversial.,In this study we developed BRAFi resistant melanoma cell lines and found that metastasis related EMT properties of BRAFi resistant cells were enhanced significantly.,Upregulation of EGFR was observed in BRAFi resistant cell lines and patient tumors due to demethylation of EGFR regulatory DNA elements.,EGFR induced PI3K/AKT pathway activation in BRAFi resistant cells through epigenetic regulation.,Treatment of EGFR inhibitor was effective in BRAFi resistant melanoma cell lines.,The study demonstrates that EGFR epigenetic activation has important implications in BRAFi resistance in melanoma.
Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma.,The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.,In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks.,Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously.,Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose.,Polymorphisms in immune-related genes were also evaluated.,Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma.,No associations between genetic polymorphisms and clinical activity were observed.,Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005).,Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.,Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity.,The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy.,Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.