ABSTRACT
BACKGROUND: Combination treatments targeting the MEK-ERK pathway and checkpoint inhibitors have improved overall survival in melanoma. Resistance to treatment especially in the brain remains challenging, and rare disease subtypes such as acral melanoma are not typically included in trials. Here we present analyses from longitudinal sampling of a patient with metastatic acral melanoma that became resistant to successive immune and targeted therapies. METHODS: We performed whole-exome sequencing and RNA sequencing on an acral melanoma that progressed on successive immune (nivolumab) and targeted (dabrafenib) therapy in the brain to identify resistance mechanisms. In addition, we performed growth inhibition assays, reverse phase protein arrays and immunoblotting on patient-derived cell lines using dabrafenib in the presence or absence of cerebrospinal fluid (CSF) in vitro. Patient-derived xenografts were also developed to analyse response to dabrafenib. RESULTS: Immune escape following checkpoint blockade was not due to loss of tumour cell recognition by the immune system or low neoantigen burden, but was associated with distinct changes in the microenvironment. Similarly, resistance to targeted therapy was not associated with acquired mutations but upregulation of the AKT/phospho-inositide 3-kinase pathway in the presence of CSF. CONCLUSION: Heterogeneous tumour interactions within the brain microenvironment enable progression on immune and targeted therapies and should be targeted in salvage treatments.
Subject(s)
Melanoma , Skin Neoplasms , Brain , Humans , Immunotherapy , Melanoma/drug therapy , Molecular Targeted Therapy , Tumor MicroenvironmentABSTRACT
The last 4 years have seen dramatic changes in the treatment of advanced melanoma, largely based on advances in targeted therapy and immunotherapy. This article examines the role of chemotherapy in the modern management of melanoma. We examine the evidence for promising new agents and discuss their position in the sequencing of treatment options for patients with advanced disease. In addition, we discuss the combination of chemotherapy with targeted treatments and immune therapies. Finally, we discuss future areas of research for ensuring that we maximize the potential of all agents available to us and identify new, effective treatments.
