The composition of the intestinal microbiota influences the development of inflammatory disorders.,However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition.,Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis.,Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development.,We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis.,Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis.,Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy.,A subset of cancer patients treated with immune checkpoint blockade develops colitis.,Here the authors show that lower abundance of Bacteroidetes and vitamin B biosynthetic modules in fecal samples of melanoma patients can predict their susceptibility to colitis following anti-CTLA-4 treatment.
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.