The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
BRAF V600E Disrupts AZD6244-Induced Abrogation of Negative Feedback Pathways between Extracellular Signal-Regulated Kinase and Raf Proteins
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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“The rationale for this combination is predicated on evidence that KRAS-mutant tumour cells are inherently resistant to MEK inhibitors owing to RAF-mediated MEK activation (Fig. 1), which might be abrogated by simultaneous inhibition of mutant KRAS143,144.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [143]
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1 retracted
RETRACTED: Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis
Tai, Y.-T., Fulciniti, M., Hideshima, T., Song, W., Leiba, M., Li, X.-F., Rumizen, M., Burger, P., Morrison, A., Podar, K., et al. (2007) · Blood · doi:10.1182/blood-2007-03-081240 · Cited by 109
RetractedMutations of the BRAF gene in human cancer
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674
Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF
Wan, P., Garnett, M. J., Roe, S. M., Lee, S., Niculescu‐Duvaz, D., Good, V. M., Cancer Genome Project, Jones, C. M., Marshall, C. J., Springer, C. J., et al. (2004) · Cell · doi:10.1016/s0092-8674(04)00215-6 · Cited by 2,863
BRAF mutation predicts sensitivity to MEK inhibition
Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G. A., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., et al. (2005) · Nature · doi:10.1038/nature04304 · Cited by 1,326
BRAF mutation in thyroid cancer
Xing, M. (2005) · Endocrine Related Cancer · doi:10.1677/erc.1.0978 · Cited by 1,293
BRAF and RAS mutations in human lung cancer and melanoma.
Brose, M. S., Volpe, P., Feldman, M. D., Kumar, M. S., Rishi, I., Gerrero, R. M., Einhorn, E., Herlyn, M., Minna, J. D., Nicholson, A. G., et al. (2002) · PubMed · Cited by 1,048
Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo
Sebolt, J. S., Dudley, D. T., Herrera, R., Becelaere, K. V., Wiland, A. M., Gowan, R. C., Tecle, H., Barrett, S. D., Bridges, A. J., Przybranowski, S. A., et al. (1999) · Nature Medicine · doi:10.1038/10533 · Cited by 972
Roux, P. P., Ballif, B. A., Anjum, R., Gygi, S. P., & Blenis, J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405659101 · Cited by 750
Regulation of Raf-1 by direct feedback phosphorylation.
Dougherty, M., Müller, J., Ritt, D. A., Zhou, M., Zhou, X.-Z., Copeland, T., Conrads, T., Veenstra, T., Lu, K., & Morrison, D. (2005) · Molecules and Cells · doi:10.1016/j.molcel.2004.11.055 · Cited by 663
Ohren, J. F., Chen, H., Pavlovsky, A. G., Whitehead, C. E., Zhang, E., Kuffa, P., Yan, C., McConnell, P., Spessard, C., Banotai, C. A., et al. (2004) · Nature Structural & Molecular Biology · doi:10.1038/nsmb859 · Cited by 635
Research works printed but not linked: 2
- Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA. Suppression of BRAFV599E in human melanoma abrogates transformation. Cancer Res 2003; 63: 5198–202.
- Yeh T, Wallace E, Lyssikatos J, Winkler J. ARRY-142886, a potent and selective MEK inhibitor. II. Potency against cellular MEK leads to inhibition of cellular proliferation and induction of apoptosis in cell lines with mutant Ras or B-Raf. Proc Am Assoc Cancer Res 2004; 45: 3889.
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RAS-targeted therapies: is the undruggable drugged?
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Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies
Bahar, M. E., Kim, H. J., & Kim, D. R. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01705-z · Cited by 888
MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road
Caunt, C. J., Sale, M. J., Smith, P. D., & Cook, S. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4000 · Cited by 606
Self-citationChappell, W. H., Steelman, L. S., Long, J. M., Kempf, R. C., Abrams, S. L., Franklin, R. A., Bäsecke, J., Stivala, F., Donia, M., Fagone, P., et al. (2011) · Oncotarget · doi:10.18632/oncotarget.240 · Cited by 510
The current state of the art and future trends in RAS-targeted cancer therapies
Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549
Metadata
- 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)
- Venue
- Cancer Research
- Published
- 2008-08-01
- Volume
- 68
- Issue
- 15
- Pages
- 6145-6153
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- 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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