Abstract
Simple SummaryPatients with advanced melanoma are often treated with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors. Although these agents prolong life, patients inevitably develop resistance and their cancer progresses. This review examines all of the potential ways that melanoma cells develop resistance to BRAF inhibitors. These mechanisms involve genetic and epigenetic changes that activate different signaling pathways, thereby bypassing the effect of BRAF inhibition, but they also involve a change in cell phenotype and the suppression of anticancer immune responses. Currently, BRAF inhibitor resistance can be partially overcome by combining a BRAF inhibitor with a mitogen-activated protein kinase kinase (MEK) inhibitor, but many other combinations are being tested. Eventually, it may be possible to choose the best combination of drugs based on the genetic profile of an individual’s cancer.This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of ‘escape routes’, so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.
Highlights
Melanoma is the least common type of skin cancer, it is the most deadly [1], causing approximately 61,000 deaths per year around the world [2]
Testing for BRAF mutations is globally recommended in order to choose the most appropriate therapy for patients with stage III or IV melanoma [7,8]
A more in-depth review of the articles meant that additional articles were excluded as being either not relevant or not an included article type, and some articles were reclassified into another topic section
Summary
Melanoma is the least common type of skin cancer, it is the most deadly [1], causing approximately 61,000 deaths per year around the world [2]. In patients with cutaneous melanoma, almost all of these mutations affect codon 600 of exon 15 [3]. Other BRAF mutations include V600D and V600R (together accounting for ~3%) These mutations are oncogenic drivers that cause tumor progression and metastasis, and their discovery led to the development of small molecule inhibitors of BRAF, including vemurafenib, dabrafenib and encorafenib, for the treatment of melanoma [5,6]. Testing for BRAF mutations is globally recommended in order to choose the most appropriate therapy for patients with stage III or IV melanoma [7,8]
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