Investigating the role of Microphthalmia-Associated transcription Factor M in melanoma development and drug resistance

Malignant melanoma is an aggressive cancer, and the prognosis is poor for patients with advanced disease. Currently, melanoma treatment consists of immunotherapy and therapy targeting the MAPK pathway. However, many patients do not respond, or develop treatment resistance. Identifying factors that contribute to melanoma initiation and/or drug resistance is therefore of interest. MITF-M is a master transcription factor that plays a dominant role in both melanocyte and melanoma biology, and elucidation of some of the aspects of the MITF-M protein signal pathways has been the subject of this thesis. In the first thesis project, we identified MITF-M as a master regulator of vemurafenib (BRAF inhibitor)-induced drug resistance. During vemurafenib treatment of melanoma cell lines, loss of MITF-M was found to upregulate the ERBB3 receptor and its cognate ligand NRG, both having effect on sustained growth and survival. Further, we investigated the role of MITF-M and SOX10 upon growth receptors their ligands using cell panels during development of vemurafenib-induced drug resistance. We suggest that identifying SOX10 and MITF levels prior to treatment initiation may offer a tool to overcome drug resistance or prolong combinatory treatment efficacy. In our final project, the role of MITF in the context of MC1R status was investigated, as mutations in MC1R may contribute to increased risk for melanoma. Here, we developed a cell line model for studying the signaling networks that contributes to melanoma development in individual’s carrying predisposing mutations in the MC1R gene. In conclusion, we have identified novel roles of MITF-M, contributing to increased understanding of melanoma progression and vemurafenib-induced drug resistance in melanoma