Abstract
The BRAF inhibitors vemurafenib, dabrafenib and encorafenib are used in the treatment of patients with BRAF-mutant melanoma. They selectively target BRAF kinase and thus interfere with the mitogen-activated protein kinase (MAPK) signalling pathway that regulates the proliferation and survival of melanoma cells. In addition to their molecularly targeted activity, BRAF inhibitors have immunomodulatory effects. The MAPK pathway is involved in T-cell receptor signalling, and interference in the pathway by BRAF inhibitors has beneficial effects on the tumour microenvironment and anti-tumour immune response in BRAF-mutant melanoma, including increased immune-stimulatory cytokine levels, decreased immunosuppressive cytokine levels, enhanced melanoma differentiation antigen expression and presentation of tumour antigens by HLA 1, and increased intra-tumoral T-cell infiltration and activity. These effects promote recognition of the tumour by the immune system and enhance anti-tumour T-cell responses. Combining BRAF inhibitors with MEK inhibitors provides more complete blockade of the MAPK pathway. The immunomodulatory effects of BRAF inhibition alone or in combination with MEK inhibition provide a rationale for combining these targeted therapies with immune checkpoint inhibitors. Available data support the synergy between these treatment approaches, indicating such combinations provide an additional beneficial effect on the tumour microenvironment and immune response in BRAF-mutant melanoma.
Highlights
Melanoma is the deadliest form of skin cancer and results from the uncontrolled division of melanocytes
This review summarises the mechanisms underlying the efficacy of BRAF inhibitors in the treatment of BRAF-mutant melanoma, including their inhibitory effect on constitutively activated
Advances in the treatment of metastatic melanoma have expanded over the last decade to include approaches such as targeted molecular therapy and immunotherapy, including T-cell checkpoint inhibition
Summary
Melanoma is the deadliest form of skin cancer and results from the uncontrolled division of melanocytes. The treatment of patients with melanoma has been advanced by the development of molecular targeted therapies and immunotherapies. This is based upon the finding that carcinogenesis is dependent on genetic mutations that activate mitogenic signalling, and that established tumours usually remain dependent on these signalling pathways. A better knowledge of the genetic and epigenetic changes of BRAF mutations through gene sequencing, as well as a fuller understanding of the underlying pathogenicity of melanoma, should help direct future targeted treatments and the development of a personalised approach to patient management. BRAF kinase and consequent interference with the MAPK pathway, and their immunomodulatory role in the tumour microenvironment, leading to enhanced tumour recognition by the immune system and anti-tumour T-cell responses
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