Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence.
Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence.
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DOI：
10.1158/0008-5472.can-13-2625
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发表时间：
2014-04-15
期刊：
影响因子：
11.2
通讯作者：
Solit DB
中科院分区：
文献类型：
--
作者：
Nissan MH;Pratilas CA;Jones AM;Ramirez R;Won H;Liu C;Tiwari S;Kong L;Hanrahan AJ;Yao Z;Merghoub T;Ribas A;Chapman PB;Yaeger R;Taylor BS;Schultz N;Berger MF;Rosen N;Solit DB
黑色素瘤是一种以激活ERK的病变为特征的疾病。虽然70%的皮肤黑色素瘤在BRAF和NRAS基因中含有激活突变，但在其余30%中驱动肿瘤进展的改变在很大程度上是不确定的。Vemurafenib是RAF激酶的选择性抑制剂，其临床效用仅限于BRAF突变型肿瘤。在NRAS突变型黑色素瘤中显示出临床活性的MEK抑制剂可能在其他ERK通路依赖性环境中有效。在这里，我们研究了一组BRAF和NRAS野生型黑色素瘤细胞系，以确定驱动其转化的遗传改变及其对ERK信号传导的依赖性，以阐明MEK抑制剂治疗的候选集。一组具有高水平RAS-GTP的BRAF/RAS野生型细胞系具有NF 1（一种RAS GTP酶激活蛋白）的缺失。在这些细胞系中，MEK抑制剂PD 0325901抑制ERK磷酸化，但也减轻了RAS的反馈抑制，导致pMEK的诱导和ERK信号传导的快速反弹。相反，MEK抑制剂曲美替尼损害细胞对ERK抑制的适应性反应，导致ERK信号传导的持续抑制和显著的抗肿瘤作用。值得注意的是，在黑色素瘤中NF 1的改变经常与RAS和BRAF的改变同时发生。在BRAF（V600 E）的背景下，NF 1丢失消除了RAS激活的负反馈，导致RAS-GTP激活升高和对RAF抑制剂的耐药性，但不包括MEK抑制剂。我们的结论是，NF 1的损失是常见的皮肤黑色素瘤，并与RAS激活，MEK依赖性和抵抗RAF抑制。
Melanoma is a disease characterized by lesions that activate ERK. Though 70% of cutaneous melanomas harbor activating mutations in the BRAF and NRAS genes, the alterations that drive tumor progression in the remaining 30% are largely undefined. Vemurafenib, a selective inhibitor of RAF kinases, has clinical utility restricted to BRAF mutant tumors. MEK inhibitors, which have shown clinical activity in NRAS-mutant melanoma, may be effective in other ERK pathway-dependent settings. Here, we investigated a panel of melanoma cell lines wild-type for BRAF and NRAS to determine the genetic alteration driving their transformation and their dependence on ERK signaling in order to elucidate a candidate set for MEK inhibitor treatment. A cohort of the BRAF/RAS wild-type cell lines with high levels of RAS-GTP had loss of NF1, a RAS GTPase activating protein. In these cell lines, the MEK inhibitor PD0325901 inhibited ERK phosphorylation, but also relieved feedback inhibition of RAS resulting in induction of pMEK and a rapid rebound in ERK signaling. In contrast, the MEK inhibitor trametinib impaired the adaptive response of cells to ERK inhibition leading to sustained suppression of ERK signaling and significant antitumor effects. Notably, alterations in NF1 frequently co-occurred with RAS and BRAF alterations in melanoma. In the setting of BRAF(V600E), NF1 loss abrogated negative feedback on RAS activation resulting in elevated activation of RAS-GTP and resistance to RAF, but not MEK, inhibitors. We conclude that loss of NF1 is common in cutaneous melanoma and is associated with RAS activation, MEK-dependence and resistance to RAF inhibition.