AI Article Synopsis
- This review explores how melanoma patients develop resistance to BRAF inhibitors, focusing on genetic mutations, epigenetic changes, immune system interactions, and combination therapies.
- The study identifies common resistance mutations, such as BRAF splice variants and NRAS mutations, which reactivate cancer pathways and contribute to the tumor's growth and survival.
- It suggests that combining BRAF inhibitors with MEK inhibitors and personalizing treatments may help manage resistance and improve outcomes for patients.
Article Abstract
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, 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.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600801 | PMC |
| http://dx.doi.org/10.3390/cancers12102801 | DOI Listing |
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