Data from A Genome-Scale RNA Interference Screen Implicates NF1 Loss in Resistance to RAF Inhibition

Abstract

<div>Abstract<p>RAF inhibitors such as vemurafenib and dabrafenib block BRAF–mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with <i>BRAF</i><sup>V600E</sup>-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 <i>NF1</i>, 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. <i>NF1</i> mutations were observed in <i>BRAF</i>–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.</p><p><b>Significance:</b> This work identifies functional loss of NF1 as a mediator of resistance to RAF inhibitors in <i>BRAF</i><sup>V600E</sup>-mutant cancers. Furthermore, we nominate new therapeutic modalities to treat this mechanism of resistance. <i>Cancer Discov; 3(3); 350–62. ©2012 AACR</i>.</p><p>See related commentary by Gibney and Smalley, p. 260</p><p>This article is highlighted in the In This Issue feature, p. 239</p></div>