Kakadia Sunilkumar, Yarlagadda Naveen, Awad Ramez, Kundranda Madappa, Niu Jiaxin, Naraev Boris, Mina Lida, Dragovich Tomislav, Gimbel Mark, Mahmoud Fade
Department of Internal Medicine, Division of Hematology and Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Onco Targets Ther. 2018 Oct 17;11:7095-7107. doi: 10.2147/OTT.S182721. eCollection 2018.
Approximately 50% of melanomas harbor an activating mutation. Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with -mutated advanced melanoma. Both genetic and epigenetic alterations play a major role in resistance to BRAF inhibitors by reactivation of the MAPK and/or the PI3K-Akt pathways. The role of BRAF inhibitors in modulating the immunomicroenvironment and perhaps enhancing the efficacy of checkpoint inhibitors is gaining interest. This article provides a comprehensive review of mechanisms of resistance to BRAF and MEK inhibitors in melanoma and summarizes landmark trials that led to the FDA approval of BRAF and MEK inhibitors in metastatic melanoma.
大约50%的黑色素瘤存在激活突变。联合使用的BRAF和MEK抑制剂，如达拉非尼和曲美替尼、维莫非尼和考比替尼、恩考芬尼和比美替尼，已获美国食品药品监督管理局（FDA）批准，用于治疗携带 - 突变的晚期黑色素瘤患者。基因和表观遗传改变通过重新激活MAPK和/或PI3K - Akt途径，在对BRAF抑制剂的耐药中起主要作用。BRAF抑制剂在调节免疫微环境以及可能增强检查点抑制剂疗效方面的作用正受到关注。本文全面综述了黑色素瘤对BRAF和MEK抑制剂的耐药机制，并总结了使BRAF和MEK抑制剂获FDA批准用于转移性黑色素瘤治疗的标志性试验。
