Abstract
According to clinical trials, BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most promising chemotherapy regimens for the treatment of advanced BRAF-mutant melanoma, though the rate of BRAF mutation gene-bearing cutaneous melanoma is limited, especially in the Asian population. In addition, drug resistance sometimes abrogates the persistent efficacy of combined therapy with BRAF and MEK inhibitors. Therefore, recent pre-clinical study-based clinical trials have attempted to identify optimal drugs (e.g., immune checkpoint inhibitors or histone deacetylase (HDAC) inhibitors) that improve the anti-melanoma effects of BRAF and MEK inhibitors. In addition, the development of novel protocols to avoid resistance of BRAF inhibitors is another purpose of recent pre-clinical and early clinical trials. This review focuses on pre-clinical studies and early to phase III clinical trials to discuss the development of combined therapy based on BRAF inhibitors for BRAF-mutant advanced melanoma, as well as mechanisms of resistance to BRAF inhibitors.
Highlights
RAF proteins are regulators of the ERK MAP kinase signaling cascade, and interaction withRAS-GTP at the membrane promotes RAF kinase activation and leads to activation of phosphorylation of MEK1 and MEK2 [1], which play significant roles in melanoma cell proliferation, leading to high responses rates to BRAF inhibitors in melanomas compared to cytotoxic drugs [2,3,4,5,6]
This review focuses on pre-clinical studies and early to phase III clinical trials to discuss the development of combined therapy based on BRAF inhibitors for BRAF-mutant advanced melanoma, as well as mechanisms of resistance to BRAF inhibitors
Activated BRAF is expressed in several cancers, including melanoma [1], and the most common BRAF mutation leads to the substitution of a glutamic acid for valine at amino acid 600 (V600E) in the kinase domain of the protein
Summary
RAF proteins are regulators of the ERK MAP kinase signaling cascade, and interaction with. III melanoma [HR = 0.28 (95%CI: 0.12–0.66), p = 0.002] [18] Taken together, these reports suggest the significance of assessing BRAF-mutated driver genes for the selection of patients who could be treated with BRAF/MEK inhibitors, and for the prediction of the efficacy of subsequent immune therapy. Since TAMs develop sequentially from monocytes into functional macrophages and can obtain various immunosuppressive functions by the stimulation of cancer stromal factors in each differentiation stage [24], the immunomodulation of TAMs might enhance the anti-tumor effects of various drugs including BRAF/MEK inhibitors [22]. The phenotypic analysis of tumor-infiltrating leukocytes (TILs) might be important to evaluate the efficacy of immune therapy [25,26,27], and to understand the mechanisms to overcome the acquisition of resistance to BRAF inhibitors [20,21,22,23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
