Cited by 147Melanoma and MAPK PathwaysProtein Kinase Regulation and GTPase SignalingLung Cancer Treatments and Mutations

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BRAF V600E Disrupts AZD6244-Induced Abrogation of Negative Feedback Pathways between Extracellular Signal-Regulated Kinase and Raf Proteins

Friday, Bret B., Yu, Chunrong, Dy, Grace K., Smith, Paul D., Wang, Liang, Thibodeau, Stephen N., Adjei, Alex A.·2008·Cancer Research

DOI 10.1158/0008-5472.can-08-1430

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Abstract

AZD6244 (ARRY 142886) is a potent and selective mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor currently in early clinical trials. We examined the activity of AZD6244 in a panel of non–small cell lung cancer and a panel of cell lines representing many cancer types using in vitro growth assays. AZD6244 induced G0-G1 cell cycle arrest in sensitive cell lines that primarily included cells containing the BRAF V600E mutation. In these cells, G0-G1 arrest is accompanied by the up-regulation of the cell cycle inhibitors p21WAF1 and p27Kip1 and down-regulation of cyclin D1. In the majority of cell lines tested, including those with K-ras or non-V600E BRAF mutations, AZD6244 induced the accumulation of phospho-MEK, an effect not observed in the most sensitive BRAF V600E-containing cells. Accumulation of phospho-MEK in non–V600E-containing cell lines is due to abrogation of negative feedback pathways. BRAF V600E disrupts negative feedback signaling, which results in enhanced baseline phospho-MEK expression. Exogenous expression of BRAF V600E disrupts feedback inhibition but does not sensitize cells to AZD6244. Specific suppression of endogenous BRAF V600E does not confer resistance to AZD6244 but enhances sensitivity to AZD6244. Thus, our findings show that BRAF V600E marks cells with an in vitro requirement for MAPK signaling to support proliferation. These cells are exquisitely sensitive to AZD6244 (IC50, <100 nmol/L), have high baseline levels of phospho-MEK, and lack feedback inhibition between ERK and Raf. These data suggest an approach to identifying cells that may be sensitive to AZD6244 and other MEK inhibitors. [Cancer Res 2008;68(15):6145–53]

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Authors: Friday, B. B., Yu, C., Dy, G. K., Smith, P. D., Wang, L., Thibodeau, S. N., & Adjei, A. A.
Affiliations: Mayo Clinic (US)
Roswell Park Comprehensive Cancer Center (US)
AstraZeneca (United Kingdom) (GB)
ORCID: Dy, Grace K.
Smith, Paul D.
Wang, Liang
Thibodeau, Stephen N.
Adjei, Alex A.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2008-08-01
Volume: 68
Issue: 15
Pages: 6145-6153
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-08-1430
OpenAlex: W2124301770
Cited by: 146
References: 44
Citations by year: 2026: 1 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 3 · 2018: 8 · 2017: 8 · 2016: 7 · 2015: 10 · 2014: 12 · 2013: 12 · 2012: 12
FWCI: 6.30
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Funders: Mayo Clinic
Array BioPharma
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: BRAF V600E mutation, selumetinib, MEK inhibitors, MAPK signaling, non-small cell lung cancer, G0/G1 cell cycle arrest, p21, p27, cyclin D1, drug sensitivity, KRAS mutation
MeSH terms: Base Sequence, Benzimidazoles, Humans, Mutation, Down-Regulation, Polymerase Chain Reaction, DNA Primers, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Extracellular Signal-Regulated MAP Kinases, raf Kinases, Proto-Oncogene Proteins B-raf, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27

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BRAF V600E Disrupts AZD6244-Induced Abrogation of Negative Feedback Pathways between Extracellular Signal-Regulated Kinase and Raf Proteins

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