A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition
Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur 4 patients atteints d'un mélanome métastatique présentant la mutation V600E du gène BRAF, cette étude met en évidence le rôle joué par la perte du gène NF1 dans l'apparition d'une résistance à un traitement par inhibiteur de BRAF tel que le vemurafenib ou le dabrafenib
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.