Vemurafenib.
Vemurafenib.
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DOI：
10.1007/978-3-319-91442-8_6
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发表时间：
2018-01-01
期刊：
影响因子：
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通讯作者：
Eigentler, Thomas K
中科院分区：
文献类型：
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作者：
Garbe, Claus;Eigentler, Thomas K
激活BRAF突变V600 E和该密码子中的相关突变对于黑色素瘤中RAS/RAF/MEK/ERK促分裂原活化蛋白激酶（MAPK）信号通路的激活最为重要。在约40%的黑色素瘤患者中检测到BRAF V600 E突变，在约5%的黑色素瘤患者中检测到BRAF V600 K突变。MAPK通路的激活导致细胞增殖的持续刺激并抑制程序性细胞死亡。Vemurafenib（PLX 4032）被开发为用于抑制突变的丝氨酸-苏氨酸激酶BRAF的低分子量分子，并且其选择性地结合BRAF V600 E激酶的ATP结合位点并抑制其活性。维罗非尼对突变BRAF的生物化学亲和力转化为仅在BRAF突变细胞系中有效抑制ERK磷酸化和细胞增殖。在动物模型实验中，证明了vemurafenib在携带BRAF V600 E突变的细胞中实现了肿瘤消退。在携带BRAF V600 E突变的患者中进行的I、II和III期维罗非尼治疗不可切除的转移性黑色素瘤的临床试验显示，所有非预期的高客观缓解率范围为50 - 80%。中位无进展生存期从达卡巴嗪组的2个月延长至维罗非尼组的7个月，中位总生存期分别从9个月延长至14个月。一个主要问题仍然是在大多数患者中几个月后对维罗非尼治疗产生耐药性，并且已经描述了多种耐药机制。在vemurafenib治疗下，约25%的患者发展为角化棘皮瘤型皮肤鳞状细胞癌，具有低侵袭潜力，且未发生转移。该药物的总体耐受性相当好，许多患者长期接受治疗。由于其他实体瘤，如乳头状甲状腺癌，结直肠癌，非小细胞肺癌和卵巢癌同样含有BRAF突变，因此vemurafenib也在这些实体中进行了测试。将来，vemurafenib与其他激酶抑制剂和免疫疗法的组合将提高其治疗潜力。
The activating BRAF mutation V600E and related mutations in this codon are most important for the activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway in melanoma. BRAF V600E mutations have been detected in ~40% of melanoma patients and BRAF V600K mutations in ~5% of melanoma patients. Activation of the MAPK pathway results in continuous stimulation of cell proliferation and inhibits programmed cell death. Vemurafenib (PLX4032) was developed as a low-molecular-weight molecule for the inhibition of the mutated serine-threonine kinase BRAF, and it selectively binds to the ATP-binding site of BRAF V600E kinase and inhibits its activity. The biochemical affinity of vemurafenib for mutated BRAF translates to potent inhibition of ERK phosphorylation and of cell proliferation exclusively in BRAF-mutant cell lines. In animal model experiments, it was demonstrated that vemurafenib achieved tumour regressions in cells harbouring the BRAF V600E mutation. The clinical trials with vemurafenib in unresectable metastatic melanoma in phases I, II and III for patients harbouring BRAF V600E mutations demonstrated all unexpected high objective response rates ranging between 50 and 80%. Median progression-free survival was prolonged from 2 months with dacarbazine to 7 months with vemurafenib, and median overall survival was, respectively, prolonged from 9 to 14months. A major problem remains in the development of resistance to vemurafenib treatment after several months in the majority of patients, and multiple resistance mechanisms have already been described. Under vemurafenib treatment, about 25% of patients developed cutaneous squamous cell carcinomas of the keratoacanthoma type with low invasive potential and without the occurrence of metastasis. The overall tolerability of the drug was quite good, and many patients remained on treatment for long times. As other solid tumours like papillary thyroid cancer, colorectal cancer, non-small-cell lung cancer and ovarian cancer likewise harbour BRAF mutation, vemurafenib is also tested in these entities. In future, combinations of vemurafenib with other kinase inhibitors and with immunotherapies will improve its therapeutic potential.