Significance of BRAF Kinase Inhibitors for Melanoma Treatment: From Bench to Bedside

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.

Keywords: BRAF inhibitors; BRAF resistance; BRAF-mutant metastatic melanoma; HDAC inhibitors; MEK inhibitors; immune checkpoint inhibitors.

Figure 1

Efficacy and adverse events of combined therapy of BRAF inhibitors plus MEK inhibitors. DT: Dabrafenib plus trametinib therapy; VC: Vemurafenib plus cobimetinib therapy; EB: Encolafenib plus binimetinib therapy; OS: Overall survival; LFT: Liver function test; SCC: Squamous cell carcinoma.