title: A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Whittaker
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Theurillat
authors.forename: Eliezer
authors.initials: E
authors.lastname: Van Allen
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.forename: Jessica
authors.initials: J
authors.lastname: Hsiao
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D025542:Neurofibromin 1 / Q000172:deficiency* / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference
chemical_list: D025542:Neurofibromin 1; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf