The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma.
The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma.
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DOI：
10.1080/17460441.2016.1201057
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发表时间：
2016-09
影响因子：
6.3
通讯作者：
Cohen MS
中科院分区：
文献类型：
--
作者：
Kim A;Cohen MS
在精准医学和复杂的现代遗传学时代，BRAFV600抑制剂维莫非尼的发现迅速成为黑色素瘤靶向治疗的典范。早在 2002 年，大多数转移性黑色素瘤就被描述为含有 BRAFV600 突变，这为人们对针对这种蛋白质作为新型治疗策略的兴趣爆发奠定了基础。高选择性 BRAFV600 抑制剂维莫非尼 (vemurafenib) 最初是通过大规模药物筛选发现的。在这里，我们回顾了维莫非尼从发现到临床应用治疗转移性黑色素瘤的历程。涵盖的主题包括临床前数据、单药 1,2 和 3 期临床试验、耐药问题和机制、不良反应（包括鳞状细胞癌的发展）以及联合试验。由于其耐受性、低毒性、快速肿瘤反应以及 BRAFV600 突变黑色素瘤患者预后的改善，维莫非尼通过临床试验迅速取得进展，并于 2011 年获得 FDA 批准。虽然其疗效已有充分证明，但对于大多数在大约 6-8 个月内出现治疗耐药的患者来说，耐久性已成为一个问题。此外，在服用该药物的患者中观察到的令人担忧的毒性包括局部皮肤鳞状细胞癌（SCC）的发展。据推测，耐药性和鳞状细胞癌的发展是由蛋白质信号传导途径（特别是 MAPK）类似的矛盾激活引起的。这些机制的识别导致了涉及新组合疗法的额外治疗策略。
In the era of precision medicine and sophisticated modern genetics, the discovery of the BRAFV600 inhibitor, vemurafenib, quickly became the model for targeted therapy in melanomas. As early as 2002, the majority of metastatic melanomas were described to harbor the BRAFV600 mutation, setting the stage for an explosion of interest for targeting this protein as a novel therapeutic strategy. The highly selective BRAFV600 inhibitor, vemurafenib, was identified initially through a large-scale drug screen. Here we examine vemurafenib's journey from discovery to clinical use in metastatic melanoma. Topics covered include preclinical data, single agent Phase 1,2 and 3 clinical trials, resistance issues and mechanisms, adverse effects including the development of squamous cell cancers, and combination trials. Due to its tolerance, low toxicity profile, rapid tumor response, and improved outcomes in melanoma patients with BRAFV600 mutations, vemurafenib was advanced rapidly through clinical trials to receive FDA approval in 2011. While its efficacy is well documented, durability has become an issue for most patients who experience therapeutic resistance in approximately 6-8 months. In addition, a concerning toxicity observed in patients taking the drug include development of localized cutaneous squamous cell carcinomas (SCCs). It is hypothesized that drug resistance and SCC development result from a similar paradoxical activation of protein signaling pathways, specifically MAPK. Identification of these mechanisms has led to additional treatment strategies involving new combination therapies.