PO-483 Phenotype switching as an escape mechanism to targeted therapies in melanoma

Introduction Melanoma is an aggressive skin cancer with increasing incidence worldwide. The development of BRAF kinase inhibitors as targeted treatments for patients with BRAF-mutant tumours and the introduction of immunotherapies contributed profoundly to an improved overall survival of patients with metastatic melanoma. Despite these promising results, the emergence of rapid resistance to these therapeutic approaches remains a serious clinical issue. Material and methods To investigate the impact of BRAF inhibitors on miRNomes and transcriptomes, we used in vitro melanoma models consisting of BRAF inhibitor-sensitive and -resistant cell lines generated in our laboratory. Subsequently, miRNA and gene expression analyses were performed in order to identify the underlying mechanisms of resistance. Results and discussions Regarding miRNome and transcriptome changes, the long-term effects of BRAF inhibition differed in a cell line-specific manner with the two different BRAF inhibitors inducing comparable responses in drug-sensitive melanoma cell lines. Despite this heterogeneity, several miRNAs (e.g. miR-100–5 p) and genes (e.g. AXL) were distinctly differentially expressed in drug-resistant versus -sensitive cell lines. Analyses of co-expressed miRNAs, as well as inversely correlated miRNA-mRNA pairs, revealed a switch from a MITF high to an AXL high ratio in a subset of drug-resistant melanoma cell lines that might be regulated by miRNAs. Additionally, the inhibition of AXL reduces growth of BRAF inhibitor-resistant melanoma cells, thus the combined inhibition of BRAF and AXL might be beneficial for patients with metastatic melanoma. Conclusion In this study, promising miRNAs and genes were identified and associated to BRAF inhibitor-mediated resistance in melanoma, and might be considered as prognostic and/or diagnostic resistance biomarkers in melanoma drug resistance.