Upstream MAPK pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients.
Upstream MAPK pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients.
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上游 MAPK 通路抑制：晚期黑色素瘤患者先使用 MEK 抑制剂，然后使用 BRAF 抑制剂。
DOI：
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
R. Dummer
中科院分区：
文献类型：
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作者：
S. Goldinger;Carla Murer;P. Stieger;R. Dummer
9071背景：在约60%的所有转移性黑色素瘤（mM）中存在激活BRAF突变已经导致开发了（i）靶向RAF和MEK激酶的抑制剂。MEK是BRAF的下游效应子。然而，由于耐药机制的发展，MAPK途径的阻断是有限的。MEK抗性可赋予对BRAF抑制的交叉抗性，而BRAF抗性独立于MAPK途径。因此，通过BRAFi开始MAPK途径抑制似乎是合理的。用MEKi随后BRAFi逆转治疗开始时的上游抑制尚未进行临床探索。方法：苏黎世大学医院皮肤科携带BRAF突变的mM患者组成研究队列。患者被分为一组，首先接受BRAFi（vemurafenib或LGX 818）治疗，然后接受MEKi（AZD 6244，trametinib或MEK 162）治疗，另一组首先接受MEKi治疗，然后接受BRAFi治疗。
9071 Background: The presence of activating BRAF mutations in about 60% of all metastatic melanomas (mM) has led to the development of inhibitors (i) targeting the RAF and MEK kinases. MEK is the downstream effector of BRAF. However, the blockage of the MAPK pathway is limited due to the development of resistance mechanisms. MEK resistance can confer cross-resistance to BRAF inhibition, whereas BRAF resistance is independent from the MAPK pathway. Hence, it seems reasonable to start a MAPK pathway inhibition by a BRAFi. An upstream inhibition beginning the treatment reversed with a MEKi followed by a BRAFi has not yet been clinically explored. Methods: Patients at the Dermatology Department of the University Hospital of Zurich with mM harboring a BRAF mutation formed the study cohort. Patients were divided into a group who was treated initially with a BRAFi (vemurafenib or LGX818) followed by a MEKi (AZD6244, trametinib, or MEK 162), and a group who first received a MEKi and was later treated with a BRAFi...