Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 50, Pages 41797-41807Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.390906
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Funding
- National Institutes of Health [GM067893, CA125103]
- Pennsylvania Commonwealth Universal Research Enhancement [AF0301]
- Department of Defense Grant [CA101019]
- Outrun the Sun
- Joanna M. Nicolay Melanoma Research Foundation
- National Cancer Institute [1P30CA56036]
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ERK1/2 signaling is frequently dysregulated in tumors through BRAF mutation. Targeting mutant BRAF with vemurafenib frequently elicits therapeutic responses; however, durable effects are often limited by ERK1/2 pathway reactivation via poorly defined mechanisms. We generated mutant BRAF(V600E) melanoma cells that exhibit resistance to PLX4720, the tool compound for vemurafenib, that co-expressed mutant (Q61K) NRAS. In these BRAF(V600E)/NRAS(Q61K) co-expressing cells, reactivation of the ERK1/2 pathway during PLX4720 treatment was dependent on NRAS. Expression of mutant NRAS in parental BRAF(V600) cells was sufficient to by-pass PLX4720 effects on ERK1/2 signaling, entry into S phase and susceptibility to apoptosis in a manner dependent on the RAF binding site in NRAS. ERK1/2 activation in BRAF(V600E)/NRAS(Q61K) cells required CRAF only in the presence of PLX4720, indicating a switch in RAF isoform requirement. Both ERK1/2 activation and resistance to apoptosis of BRAF(V600E)/NRAS(Q61K) cells in the presence of PLX4720 was modulated by SHOC-2/Sur-8 expression, a RAS-RAF scaffold protein. These data show that NRAS mutations confer resistance to RAF inhibitors in mutant BRAF cells and alter RAF isoform and scaffold molecule requirements to re-activate the ERK1/2 pathway.
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