A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition.
A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition.
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DOI：
10.1158/2159-8290.cd-12-0470
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发表时间：
2013-03
期刊：
影响因子：
28.2
通讯作者：
Garraway LA
中科院分区：
文献类型：
--
作者：
Whittaker SR;Theurillat JP;Van Allen E;Wagle N;Hsiao J;Cowley GS;Schadendorf D;Root DE;Garraway LA
RAF抑制剂，例如vemurafenib和dabrafenib块B-RAF介导的细胞增殖，并在绝大多数B-RAFV600E-突变药物黑色素瘤患者中获得有意义的临床益处。但是，一些患者对该方案没有反应，几乎所有患者都对治疗性抗性进行了进展。我们采用了一个合并的RNA干扰屏幕靶向> 16,500个基因，以发现功能事件的丧失，这些事件可能会导致对RAF抑制的抵抗力。排名最高的基因是NF1，它编码神经纤维蛋白，这是一种抑制RAS活性的肿瘤抑制剂。 NF1损耗通过持续的MAPK途径激活介导对RAF和MEK抑制剂的抗性。然而，缺乏NF1的细胞保留了对不可逆的RAF抑制剂AZ628和ERK抑制剂的敏感性。在B-RAF突变剂肿瘤细胞中观察到NF1突变，这些肿瘤细胞本质上对RAF抑制作用以及从表现出对vemurafenib耐药性的患者获得的黑色素瘤肿瘤中，因此证明了NF1驱动的RAF/MEK-MEK-TARGET疗法的临床潜力。
RAF inhibitors such as vemurafenib and dabrafenib block B-RAF-mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with B-RAFV600E-mutant melanoma. However, some patients do not respond to this regimen, and nearly all progress to therapeutic resistance. We employed a pooled RNA interference screen targeting >16,500 genes to discover loss of function events that could drive resistance to RAF inhibition. The highest-ranking gene was NF1, which encodes neurofibromin, a tumor suppressor that inhibits RAS activity. NF1 loss mediates resistance to RAF and MEK inhibitors through sustained MAPK pathway activation. However, cells lacking NF1 retained sensitivity to the irreversible RAF inhibitor AZ628 and an ERK inhibitor. NF1 mutations were observed in B-RAF-mutant tumor cells that are intrinsically resistant to RAF inhibition and in melanoma tumors obtained from patients exhibiting resistance to vemurafenib, thus demonstrating the clinical potential for NF1-driven resistance to RAF/MEK-targeted therapies.