Vemurafenib
Vemurafenib
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DOI：
10.1007/978-3-642-54490-3_13
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发表时间：
2014-01-01
期刊：
影响因子：
--
通讯作者：
Eigentler, Thomas K.
中科院分区：
文献类型：
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作者：
Garbe, Claus;Abusaif, Sail;Eigentler, Thomas K.
在黑色素瘤中，激活的BRAF突变V600E及其相关突变对于激活Ras/RAF/MEK/ERK丝裂原活化蛋白激酶(MAPK)信号通路至关重要。在40%的黑色素瘤患者中检测到BRAF V600E突变，在5%的黑色素瘤患者中检测到BRAF V600K突变。MAPK通路的激活可持续刺激细胞增殖，抑制细胞程序性死亡。维莫拉非尼(PLX4032)是一种用于抑制突变的丝氨酸苏氨酸激酶BRAF的低分子分子，它选择性地结合BRAF-V600E激酶的ATP结合部位并抑制其活性。维莫拉非尼对突变的BRAF的生化亲和力转化为对ERK磷酸化的有效抑制，并仅在BRAF突变的细胞系中抑制细胞增殖。在动物模型实验中，已经证明维莫拉非尼在含有BRAF V600E突变的细胞中实现了肿瘤的消退。对于携带BRAF V600E突变的患者，使用维莫拉非尼治疗I、II和III期无法切除的转移性黑色素瘤的临床试验表明，所有意想不到的高客观应答率都在50%到80%之间。中位无进展生存期从服用达卡巴肼的2个月延长到服用维莫拉非尼的7个月，中位总生存期分别从9个月延长到14个月。仍然存在的一个主要问题是大多数患者在几个月后对维莫拉非尼治疗产生耐药性，并且已经描述了多种耐药机制。在维莫拉非尼治疗下，大约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，并且没有发生转移。该药总体耐受性相当好，多名患者长期坚持治疗。由于其他实体肿瘤，如乳头状甲状腺癌、结直肠癌、非小细胞肺癌和卵巢癌也存在BRAF突变，维莫拉非尼也在这些实体中进行了测试。未来，维莫拉非尼与其他激酶抑制剂和免疫疗法的联合使用将提高其治疗潜力。
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 similar to 40 % of melanoma patients and BRAF V600K mutations in similar to 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 phase 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 two months with dacarbazine to seven months with vemurafenib, and median overall survival was respectively prolonged from 9 to 14 months. A major problem that remains is 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 occurrence of metastasis. The overall tolerability of the drug was quite good, and a number of 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.