基于靶标BRAF的抗肿瘤研究进展

Progress of anti-tumor study based on BRAF

BRAF是人类最重要的原癌基因之一,大约8%的人类肿瘤发生BRAF突变。BRAF绝大部分突变形式为BRAFV600E突变,主要发生于黑色素瘤、结肠癌和甲状腺癌中。该突变导致下游MEK-ERK信号通路持续激活,对肿瘤的生长增殖和侵袭转移至关重要,是抗黑色素瘤等V600E突变肿瘤的有效作用靶标之一。2011年,首个BRAFV600E靶向抑制剂威罗菲尼被FDA批准上市,用于治疗BRAFV600E突变的晚期黑色素瘤患者,有效延长了患者无进展生存期及总生存期,取得了突破性的治疗效果,也是典型的基于基因诊断选择用药的靶向治疗药物。但是耐药性的出现使得药物治疗效果受到限制,其耐药机制、新药物开发以及预防或延缓耐药的研究成为目前需要解决的关键问题。本文介绍了BRAFV600E突变体作为抗肿瘤靶标的依据以及其抑制剂的研究状况,分析了BRAFV600E靶向药物的耐药机制,并指出了目前解决耐药性问题的方向。

BRAF is one of the most important pro-oncogenes, which is mutated in approximately 8% of human tumors. The most common BRAF mutation is a valine-to-glutamate transition （V600E） that is expressed primarily in melanoma, colorectal cancer and thyroid carcinoma. MEK/ERK is constitutively activated in the cells expressing BRAFV600E, leading to tumor development, invasion, and metastasis. Therefore, BRAFV600E is a therapeutic target for melanoma and some other BRAFV600E tumors. Vemurafenib, a BRAFV600E inhibitor, which was approved by FDA for the treatment of late-stage melanoma in 2011, produces improved rates of overall and progression-free survival in patients with the BRAFV600E mutation, making a dramatic breakthrough in melanoma treatment. Vemurafenib is also an individual target drug based on genetic diagnosis. However, its therapeutic success is limited by the emergence of drug resistance. Therefore, it is important to explore the mechanisms underlying the resistance for developing new inhibitor drugs and for preventing or delaying the resistance evolution to BRAF inhibitor drugs. In this review, we described the role of BRAFV600E as an anti-tumor drug target and the development of BRAF inhibitors. We also discussed the mechanisms leading to resistance of BRAFV600E inhibitors. Furthermore, therapeutic strategies that might be employed to overcome acquired resistance were proposed.