Oral Presentation ASDR-AWTRS-MEPSA 2018 Joint Meeting

Phenotype heterogeneity in melanoma therapy and progression (#6)

Claudia Wellbrock 1
  1. University of Manchester, Manchester, United Kingdom

Current melanoma therapies are primarily based on targeting immune check-points in order to reactivate the immune response, or targeting the BRAF-kinase and the MAPK-pathway in melanomas carrying a BRAF mutation (app. 50%). Immunotherapy carries tremendous promise, but responses are not immediate and toxicity is high. MAPK-pathway inhibitors can induce fast responses with minimal adverse effects, but acquired resistance occurs more frequently than with immunotherapy. We and others have shown that intra-tumour signalling between melanoma cells and non-tumour cells has a major impact on the efficacy of MAP-kinase pathway targeting drugs and the development of resistance. In addition, cell-autonomous resistance to MAPK-pathway therapy can be produced by various factors, and we discovered that the melanoma-specific transcription factor MITF, which is also an essential survival factor for drug-addicted acquired resistant melanomas is one of them.

An additional challenge for all current therapies is posed by the phenotype heterogeneity found in heterogeneous melanomas. The two major melanoma-phenotypes are represented by ‘non-EMT like’ MITFhigh and ‘EMT-like’ MITFlow subpopulations and it is thought that transcriptional plasticity of these phenotypes not only contributes to the development of therapy resistance, but also drives melanoma progression. However, we have discovered that additional complexity comes from co-operative interactions between MITFhigh and MITFlow phenotypes in heterogeneous tumours. We identified a novel mechanism based on intra-tumour communications that maintains phenotype heterogeneity, and targeting this mechanism overcomes heterogeneity driven resistance to BRAF inhibitors. We also found that co-operativity between MITFhigh- and MITFlow-subpopulations accelerates tumour growth and invasion, supports circulating melanoma cells (CTCs) and is instrumental to founding heterogeneous metastases.