Abstract
The mitogen‐activated protein kinase (MAPK) signaling pathway plays a significant role in mediating cellular physiological activities, such as proliferation, differentiation, apoptosis, and senescence. This signaling pathway is composed of several major proto‐oncogenes of RAS/RAF/MEK/ERK, among which the BRAF proto‐oncogene, as one of the three members of the RAF family, has a higher mutation rate than ARAF and CRAF and has attracted extensive attention. Regarding the BRAF mutation, approximately 95% of BRAF mutations belong to the BRAF V600E mutation, which can enhance the expression of the MAPK signaling pathway and is thus related to the occurrence and development of various malignant tumors and has been successfully identified as a therapeutic target. Moreover, drug resistance to BRAF inhibitor treatment also appears to be an important issue. Considering the successful use of BRAF inhibitors in melanoma, we provide a brief overview of the BRAF mutations, including their basic structures and activation mechanisms, and the new classification method for BRAF mutations. Most importantly, we summarize the results of BRAF inhibitor treatment in different sarcomas. To overcome drug resistance to BRAF inhibitor treatment, we also outline the different mechanisms of drug resistance to BRAF inhibitor treatment and introduce the combination strategy of BRAF inhibitors with other targeted therapies.
Highlights
The mitogen-activated protein kinase (MAPK) pathway, consisting of RAS/RAF/MEK/ERK can transfer extracellular signals, including hormones, cytokines, and growth factors, to the nucleus, changing gene expression in the cell and mediating proliferation, differentiation, survival, and apoptosis.1-5RAS comprises three isoforms: KRAS, NRAS, and HRAS.[4,6] It can be transformed between the state of activeGTP-bound and the state of inactive GDP-bound.[7]
We review the therapeutic efficacy of BRAF inhibitors in sarcomas, and summarize the mechanism of resistance to BRAF inhibitors and the combination with other targeted drugs
In the BRAF gene, a kind of splice variant that deletes a part of the exon that removes the RAS-binding domain (RBD) participates in the resistance to BRAF inhibitors by increasing the tendency to form homologous dimers and enhancing the MAPK signaling pathway.[65-67]
Summary
The mitogen-activated protein kinase (MAPK) pathway, consisting of RAS/RAF/MEK/ERK can transfer extracellular signals, including hormones, cytokines, and growth factors, to the nucleus, changing gene expression in the cell and mediating proliferation, differentiation, survival, and apoptosis.1-5RAS comprises three isoforms: KRAS, NRAS, and HRAS.[4,6] It can be transformed between the state of activeGTP-bound and the state of inactive GDP-bound.[7]. 5% of colorectal cancer patients achieve a response, which is mainly related to reactivation of the MAPK pathway caused by EGFR.[2,44] patients with colorectal cancer may be treated with other drugs, such as EGFR inhibitors.[41,44] There have been reports about the efficacy of vemurafenib in thyroid cancer, hairy cell leukemia, and lung cancer with BRAF mutations.
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