American Association for Cancer Research
21598290cd120470-sup-supplemental_figure_4_pdf_file_-_38k.pdf (38.88 kB)

Supplementary Figure 4 from A Genome-Scale RNA Interference Screen Implicates NF1 Loss in Resistance to RAF Inhibition

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posted on 2023-04-03, 20:22 authored by Steven R. Whittaker, Jean-Philippe Theurillat, Eliezer Van Allen, Nikhil Wagle, Jessica Hsiao, Glenn S. Cowley, Dirk Schadendorf, David E. Root, Levi A. Garraway

Supplementary Figure 4 PDF file - 38K, Identification of human melanoma and colorectal cancer cell lines with coincident B-RAF and NF1 mutations is associated with resistance to PLX4720. Human melanoma and colorectal cancer cell lines from the Cancer Cell Line Encyclopedia with B-RAFV600E and NF1 mutation were identified and compared to NF1 wild-type melanoma cell lines in terms of sensitivity to PLX4720, NF1 mRNA expression, NF1 copy number alterations and NF1 mutation status. In the heat map, blue represents lower values and red represents higher values, whilst NF1 mutation status is represented as wild-type: blue, point mutation: white, potential loss-of-function mutation: red



RAF inhibitors such as vemurafenib and dabrafenib block BRAF–mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with BRAFV600E-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.Significance: This work identifies functional loss of NF1 as a mediator of resistance to RAF inhibitors in BRAFV600E-mutant cancers. Furthermore, we nominate new therapeutic modalities to treat this mechanism of resistance. Cancer Discov; 3(3); 350–62. ©2012 AACR.See related commentary by Gibney and Smalley, p. 260This article is highlighted in the In This Issue feature, p. 239

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