Role of miRNAs in drug-resistance of advanced melanoma and identification of novel kinase inhibitors to overcome drug-resistance of advanced melanoma

Activating mutations in the BRAF kinase have been identified as a major driving force in >60% of melanomas. BRAF inhibitors have become the first-line treatment for patients carrying this mutation. However, these molecules are not able to provide durable responses, as resistance to the treatment develops in almost all patients, rapidly leading to a highly aggressive and untreatable form of melanoma.

In a new project funded by the Luxembourgish Fondation Cancer with 170 000 €, new kinase inhibitor combinations for overcoming this resistance will be identified through prospective pharmacological screening of kinase inhibitor libraries using BRAF inhibitor-resistant versus -sensitive melanoma cell lines. Furthermore, expression profiles of miRNAs in BRAF inhibitor-resistant versus -sensitive melanoma cell lines will be analysed in order to identify miRNAs that might be mechanistically involved in the establishment and maintenance of drug resistance. Moreover, we will characterize the changes of secreted miRNomes in the resistant clones as well as in patients with acquired or intrinsic resistance to assess their suitability as early biomarkers in the serum or plasma of drug-resistant patients. These results will provide the basis for a follow-up evaluation of (selected) miRNAs as possible biomarkers for BRAF inhibitor resistance and as potential drug targets.