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PMID: 23076151 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

SHOC2 and CRAF mediate ERK1/2 reactivation in mutant NRAS-mediated resistance to RAF inhibitor.

The Journal of biological chemistry ·Vol. 287 ·No. 50 ·2012-12-07 ·Pages 41797-807

Kaplan FM, Kugel CH, Dadpey N, Shao Y, Abel EV, Aplin AE

Abstract

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, re-activation 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.

MeSH Terms
Amino Acid Substitution Cell Line, Tumor Drug Resistance, Neoplasm/drug effects,genetics Enzyme Activation/drug effects,genetics Humans Indoles/pharmacology Intracellular Signaling Peptides and Proteins/genetics,metabolism MAP Kinase Signaling System/drug effects,genetics Mitogen-Activated Protein Kinase 1/genetics,metabolism Mitogen-Activated Protein Kinase 3/genetics,metabolism Mutation, Missense Proto-Oncogene Proteins B-raf/genetics,metabolism Proto-Oncogene Proteins c-raf/genetics,metabolism Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors,genetics,metabolism S Phase/drug effects,genetics Sulfonamides/pharmacology
Chemicals
Indoles Intracellular Signaling Peptides and Proteins PLX 4720 SHOC2 protein, human Sulfonamides BRAF protein, human Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-raf MAPK1 protein, human Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Proto-Oncogene Proteins p21(ras)
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Kaplan Fred M
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Kugel Curtis H
Dadpey Neda
Shao Yongping
Abel Ethan V
Aplin Andrew E
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M112.390906
Published
2012-12-07
Epub
2012-00-17
Pages
41797-807
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3516728
Subset
IM
Grants
NIGMS NIH HHS · R01 GM067893 · United States
NIGMS NIH HHS · GM067893 · United States
NCI NIH HHS · CA125103 · United States
NCI NIH HHS · R01 CA101019 · United States
NCI NIH HHS · CA101019 · United States
NCI NIH HHS · R01 CA125103 · United States
NCI NIH HHS · P30 CA056036 · United States
External Links
PubMed source DOI: 10.1074/jbc.M112.390906 PMC Full Text View journal details
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