BRAF V600突变在黑色素瘤中的作用。
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Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, Palmieri G, Testori A, Marincola FM, Mozzillo N
BRAF V600突变在黑色素瘤中的作用。
《翻译医学》2012年7月9日10:85。doi: 10.1186 / 1479-5876-10-85。
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22554099 (PubMed视图］
- 摘要
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BRAF是一种丝氨酸/苏氨酸蛋白激酶，激活MAP激酶/ erk信号通路。大约50%的黑素瘤携带激活BRAF突变(超过90% V600E)。BRAFV600E已涉及不同的黑色素瘤发生机制，其中大部分是由于下游MEK/ERK效应子的解除调控激活。突变型BRAF的第一个选择性抑制剂vemurafenib在I期和II期试验中获得了令人鼓舞的结果，并在未接受治疗的患者(BRIM-3)的III期试验中与达卡巴嗪进行了比较。研究结果显示，死亡风险相对降低63%，肿瘤进展风险相对降低74%。考虑到迄今为止完成的所有试验，vemurafenib的中位总生存期约为16个月，而dacarbazine的中位总生存期不到10个月。Vemurafenib已在表达BRAFV600E突变形式的黑色素瘤患者中进行了广泛的测试;它也被证明对抑制携带V600K突变的黑素瘤有效。因此，2011年FDA和EMA批准vemurafenib用于携带BRAFV600突变的转移性黑色素瘤。一些研究结果表明，局部治疗后继续vemurafenib治疗对部分疾病进展(PD)患者可能有益。 Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.
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