Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Cancer Discov. 2013 Mar;3(3):350-62. doi: 10.1158/2159-8290.CD-12-0470. Epub 2013 Jan 3.
RAF inhibitors such as vemurafenib and dabrafenib block BRAF-mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with BRAF(V600E)-mutant melanoma. However, some patients do not respond to this regimen, and nearly all progress to therapeutic resistance. We used a pooled RNA interference screen targeting more than 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 mitogen-activated protein kinase (MAPK) kinase kinase (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 BRAF-mutant tumor cells that are intrinsically resistant to RAF inhibition and in melanoma tumors obtained from patients exhibiting resistance to vemurafenib, thus showing the clinical potential for NF1-driven resistance to RAF/MEK-targeted therapies.
RAF 抑制剂（如 vemurafenib 和 dabrafenib）可阻断 BRAF 介导的细胞增殖，并在绝大多数 BRAF(V600E)-突变型黑色素瘤患者中实现显著的临床获益。然而，一些患者对此治疗方案无反应，且几乎所有患者都会产生治疗耐药性。我们使用了一个针对超过 16500 个基因的 RNA 干扰筛选库，以发现可能导致 RAF 抑制耐药的基因失活事件。排名最高的基因是 NF1，它编码神经纤维瘤蛋白，这是一种肿瘤抑制因子，可以抑制 RAS 的活性。NF1 缺失通过持续的 MAPK 通路激活介导 RAF 和丝裂原活化蛋白激酶（MAPK）激酶激酶（MEK）抑制剂的耐药性。然而，缺乏 NF1 的细胞仍然对不可逆的 RAF 抑制剂 AZ628 和 ERK 抑制剂敏感。在对 RAF 抑制具有内在耐药性的 BRAF 突变型肿瘤细胞以及对 vemurafenib 耐药的黑色素瘤肿瘤中观察到 NF1 突变，这表明 NF1 驱动的 RAF/MEK 靶向治疗耐药具有临床潜力。
