的角色BRAF V600突变在黑色素瘤。

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Grob Ascierto PA,柯克伍德JM, JJ,西蒙尼E,格里马尔迪,Maio M, Palmieri G, Testori, Marincola调频,Mozzillo N

的角色BRAF V600突变在黑色素瘤。

J Transl。2012年7月9日,10:85。doi: 10.1186 / 1479-5876-10-85。

PubMed ID

22554099 (在PubMed

]

文摘

BRAF是一种丝氨酸/苏氨酸蛋白激酶激活MAP激酶/ ERK-signaling通路。beplayapp大约50%的黑色素瘤港口激活BRAF突变V600E(超过90%)。BRAFV600E melanomagenesis涉及不同的机制,其中大部分由于管制的激活下游MEK / ERK效应器。第一BRAF基因突变的选择性抑制剂,vemurafenib后高度鼓励I和II期临床试验的结果,与达卡巴嗪在第三期临床试验首次治疗患者(BRIM-3)。研究结果显示相对降低63%的死亡风险74%,肿瘤恶化的风险。考虑到目前为止所有试验完成后,中值总体存活率达到大约16个月vemurafenib相比,不到10个月达卡巴嗪治疗。Vemurafenib广泛测试在黑色素瘤患者表达BRAFV600E突变形式;它也被证明是有效地抑制黑色素瘤V600K突变。2011年,FDA和EMA因此批准vemurafenib对于转移性黑色素瘤携带BRAFV600突变。vemurafenib的一些研究结果表明,延续治疗可能是有益的局部治疗后患者的疾病进展的一个子集(PD)。 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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Dabrafenib