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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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Cites
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
Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate
Santos, S. D. M., Verveer, P. J., & Bastiaens, P. I. H. (2007) · Nature Cell Biology · doi:10.1038/ncb1543 · Cited by 609
Yeh, T. C., Marsh, V., Bernat, B. A., Ballard, J., Colwell, H., Evans, R. J., Parry, J., Smith, D. J., Brandhuber, B. J., Gross, S. D., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1150 · Cited by 578
Wild-Type and Mutant B-RAF Activate C-RAF through Distinct Mechanisms Involving Heterodimerization
Garnett, M. J., Rana, S., Paterson, H., Barford, D., & Marais, R. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.10.022 · Cited by 416
Suppression of BRAF(V599E) in human melanoma abrogates transformation.
Hingorani, S. R., Jacobetz, M. A., Robertson, G. P., Herlyn, M., & Tuveson, D. A. (2003) · PubMed · Cited by 408
Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis
Porter, A. C., & Vaillancourt, R. R. (1998) · Oncogene · doi:10.1038/sj.onc.1202171 · Cited by 322
Mutant V599EB-Raf Regulates Growth and Vascular Development of Malignant Melanoma Tumors
Sharma, A. K., Trivedi, N. R., Zimmerman, M., Tuveson, D. A., Smith, C. D., & Robertson, G. P. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-2423 · Cited by 318
Role of the Kinase MST2 in Suppression of Apoptosis by the Proto-Oncogene Product Raf-1
O’Neill, E. E., Rushworth, L. K., Baccarini, M., & Kölch, W. (2004) · Science · doi:10.1126/science.1103233 · Cited by 317
Chen, J., Fujii, K., Zhang, L., Roberts, T. M., & Fu, H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141224398 · Cited by 316
BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair.
Wang, L., Cunningham, J. M., Winters, J. L., Guenther, J. C., French, A. J., Boardman, L. A., Burgart, L. J., McDonnell, S. K., Schaid, D. J., & Thibodeau, S. N. (2003) · PubMed · Cited by 280
Self-citationMammalian Sprouty Proteins Inhibit Cell Growth and Differentiation by Preventing Ras Activation
Groß, I., Bassit, B., Benezra, M., & Licht, J. D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m108234200 · Cited by 255
K-ras as a target for cancer therapy
Friday, B. B., & Adjei, A. A. (2005) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2005.08.001 · Cited by 248
Self-citationIn ovarian neoplasms, BRAF , but not KRAS , mutations are restricted to low‐grade serous tumours
Sieben, N. L. G., Macropoulos, P., Roemen, G. M. J. M., Kolkman-Uljee, S. M., Fleuren, G. J., Houmadi, R., Diss, T. C., Warren, B. K., Al‐Adnani, M., de Goeij, A. F. P. M., et al. (2004) · The Journal of Pathology · doi:10.1002/path.1521 · Cited by 237
Oncogenic BRAF Is Required for Tumor Growth and Maintenance in Melanoma Models
Hoeflich, K. P., Gray, D. C., Eby, M. T., Tien, J., Wong, L. L.-Y., Bower, J., Gogineni, A., Zha, J., Cole, M. J., Stern, H. M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2720 · Cited by 234
Sprouty2 Inhibits the Ras/MAP Kinase Pathway by Inhibiting the Activation of Raf
Yusoff, P., Lao, D.-H., Ong, S. H., Wong, E. S. M., Lim, J., Lo, T. L., Leong, H. F., Fong, C. W., & Guy, G. R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m108368200 · Cited by 229
Abbott, K. L., Friday, B. B., Thaloor, D., Murphy, T. J., & Pavlath, G. K. (1998) · Molecular Biology of the Cell · doi:10.1091/mbc.9.10.2905 · Cited by 226
Self-citationBRAF Is a Therapeutic Target in Aggressive Thyroid Carcinoma
Salvatore, G., Falco, V. D., Salerno, P., Nappi, T. C., Pepe, S., Troncone, G., Carlomagno, F., Melillo, R. M., Wilhelm, S. M., & Santoro, M. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-2378 · Cited by 171
Huynh, H. T., Soo, K. C., Chow, P. K. H., & Tran, E. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0436 · Cited by 150
Brown, A. P., Carlson, T., Loi, C., & Graziano, M. J. (2006) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-006-0323-5 · Cited by 127
Tsavachidou, D., Coleman, M. L., Athanasiadis, G., Li, S., Licht, J. D., Olson, M. F., & Weber, B. L. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1669 · Cited by 118
Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-Raf
Brummer, T., Naegele, H., Reth, M. G., & Misawa, Y. (2003) · Oncogene · doi:10.1038/sj.onc.1207185 · Cited by 115
ERK Pathway Positively Regulates the Expression of Sprouty Genes
Ozaki, K., Kadomoto, R., Asato, K., Tanimura, S., Itoh, N., & Kohno, M. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5295 · Cited by 113
Signaling Through RAS-RAF-MEK-ERK: from Basics to Bedside
Zebisch, A., Czernilofsky, A. P., Kéri, G., Smigelskaite, J., Sill, H., & Troppmair, J. (2007) · Current Medicinal Chemistry · doi:10.2174/092986707780059670 · Cited by 112
Ball, D. W., Jin, N. Y., Rosen, D. M., Dackiw, A. P. B., Sidransky, D., Xing, M., & Nelkin, B. D. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1184 · Cited by 109
Sapio, M. R., Posca, D., Troncone, G., Pettinato, G., Palombini, L., Rossi, G., Fenzi, G., & Vitale, M. (2006) · European Journal of Endocrinology · doi:10.1530/eje.1.02072 · Cited by 102
Brognard, J., & Dennis, P. A. (2002) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401054 · Cited by 89
Four human carcinoma cell lines with novel mutations in position 12 of c-K-ras oncogene
Valenzuela, D., & Groffen, J. (1986) · Nucleic Acids Research · doi:10.1093/nar/14.2.843 · Cited by 86
McIntyre, A., Summersgill, B. M., Spendlove, H. E., Huddart, R. A., Houlston, R. S., & SHIPLEY, J. M. (2005) · Neoplasia · doi:10.1593/neo.05514 · Cited by 78
Identification of the Anti-proliferative Protein Tob as a MAPK Substrate
Maekawa, M., Nishida, E., & Tanoue, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204506200 · Cited by 77
Ledwith, B. J., Manam, S., Kraynak, A. R., Nichols, W. W., & Bradley, M. O. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.4.1545 · Cited by 76
Delaney, A. M., Printen, J. A., Chen, H., Fauman, E. B., & Dudley, D. T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.21.7593-7602.2002 · Cited by 75
Progress Towards Therapeutic Small Molecule MEK Inhibitors for Use in Cancer Therapy
Wallace, E. M., Lyssikatos, J. P., Yeh, T. C., Winkler, J. D., & Koch, K. M. (2005) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026053507723 · Cited by 70
Meng, X. W., Chandra, J., Loegering, D. A., Becelaere, K. V., Kottke, T. J., Gore, S. D., Karp, J. E., Sebolt-Leopold, J., & Kaufmann, S. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304793200 · Cited by 54
Ras as a target in cancer therapy
Midgley, R. S., & Kerr, R. S. (2002) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(01)00189-5 · Cited by 45
Eppstein, A. C., Sandoval, J. A., Klein, P. J., Woodruff, H. A., Grosfeld, J. L., Hickey, R. J., Malkas, L. H., & Schmidt, C. M. (2006) · Journal of Pediatric Surgery · doi:10.1016/j.jpedsurg.2005.10.047 · Cited by 22
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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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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