BRAF

BRAF encodes proteins belonging to the RAF family of serine/threonine protein kinases that regulate MAPK/ ERK signaling and affect cell division, differentiation and secretion (PMID: 21441910, PMID: 29433126). Among the mutations of BRAF, V600 mutation belongs class Ⅰ, which is independent of RAS and can be activated as an independent monomer or upstream of RAS, and is sensitive to current RAF monomer inhibitors. Class Ⅱ BRAF mutation (K601E, K601N, K601T, etc.) is independent of RAS and send signal as a constituent dimer (PMID: 28783719). V600E and V600K are the most common oncogenic mutations in melanoma, and have also been associated with other cancers, including Non-Hodgkin's lymphoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, hair cell leukemia, and lung adenocarcinoma (PMID: 23594689). Mutations in BRAF have also been associated with Noonan and Costello syndrome. The frequency of the BRAF V600E mutation in histiocytosis of ECD patients is 54% (PMID:30120160).

Vemurafenib is the first FDA approved selective BRAF inhibitor, which binds to the ATP binding domain of BRAF mutants (such as V600E, V600R and V600D) to inhibit tumor cell growth. Dabrafenib, a type Ⅰ kinase inhibitor, is the second BRAF inhibitor approved by FDA. This reversible ATP competitive inhibitor inhibits BRAF V600E, V600D, and V600K (PMID: 23251089). It can be used as a single agent or combined with trametinib (PMID: 23918947) with a better progression-free survival than decarbazine (PMID: 22735384). Encorafenib is a selective oral BRAF inhibitor for BRAF V600E that was approved by the FDA in combination with the MEK inhibitor binimetinib (MEK162) for the treatment of patients with metastatic melanoma with BRAF V600E mutations. The Phase Ⅱ trial (NCT02631447) was used to determine the best treatment modalities for BRAFi + MEKi (Encorafenib + Binimetinib) and immunoregulatory antibody (ipilimumab + nivolumab) in patients with stage III-IV metastatic BRAF V600 melanoma. The addition of MEK and BRAF inhibitors delays the development of resistance and reduces the toxicity associated with BRAF inhibitor monotherapy. Vemurafenib and dabrafenib are potent and selective inhibitors of melanoma cell lines induced by BRAF kinase V600 mutations that block ERK phosphorylation and cell proliferation, and induce G1 cell cycle arrest and apoptosis (PMID: 20668238, PMID: 20668238, PMID: 24900673, PMID: 18287029). But there is no effect in wild type or non-V600 mutations. Encorafenib targets V600E and V600K mutants and has some inhibition against wild-type BRAF mutations (PMID: 28611198). Trametinib/GSK1120212 is a reversible, non-ATP-competitive MEK1/2 inhibitor approved by the FDA. Dabrafenib and trametinib, cobimetinib/GDC-0973 and vemurafenib, and binimetinib/MEK162 in combination with encorafenib, was approved to be used for patients with metastatic BRAF V600E/K melanoma (PMID: 28475671, NCT01689519). ERK has more than 100 substrates, some of which involve MAPK/ERK activation/deactivation feedback loops, but it has only one upstream effector, MEK1/2. Due to this effect, ERK inhibitors are promising as a way to overcome BRAF V600E melanoma resistance and reactivation of BRAF or MEK inhibitor. Ulixertinib is a novel selective ERK1/2 inhibitor that inhibits ERK1/2 in a reversibly competitive manner, and ulixertinib shows the same efficacy in BRAF mutated cells and BRAF + MEK dual mutated cells. However, the efficacy of BRAF and MEK inhibitors decreased in dual mutant lines (PMID: 28939558). Currently, it has been designated by the FDA for rapid treatment of metastatic BRAF V600E mutant melanoma (PMID: 29247021). According to the observation of BRAF V600E mutant melanoma, inhibitors of BRAF and MEK have double inhibitory effect on MAPK pathway. Dabrafenib and trametinib combination in BRAF V600E mutations in patients with non-small cell lung cancer (NSCLC) is a powerful antitumor activity and the safety of the controllable (PMID: 29438093, PMID: 29595366, PMID: 28919012), also can be used in BRAF V600E mutant anaplastic thyroid cancer with good clinical activity. BRAF V600E inhibition leads to rapid feedback activation of EGFR, leading to continuous proliferation of tumor cells (PMID:22281684). The combination of MAPK and MEK is more effective than the combination of anti-EGFR agents and BRAF inhibitors. The combination of encorafenib, binimetinib and cetuximab is effective in the treatment of patients with BRAF V600E mutant metastatic colorectal cancer (PMID: 30892987). Vemurafenib, an oral monotherapy targeting BRAF mutations, is the first FDA approved treatment for Erdheim-Chester disease (ECD) (PMID:30120160).