Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244)

Dry, Jonathan R.; Pavey, Sandra; Pratilas, Christine A.; Harbron, Chris; Runswick, Sarah; Hodgson, Darren; Chresta, Christine; McCormack, Rose; Byrne, Natalie; Cockerill, Mark; Graham, Alexander; Beran, Garry; Cassidy, Andrew; Haggerty, Carolyn; Brown, Helen; Ellison, Gillian; Dering, Judy; Taylor, Barry S.; Stark, Mitchell; Bonazzi, Vanessa; Ravishankar, Sugandha; Packer, Leisl; Xing, Feng; Solit, David B.; Finn, Richard S.; Rosen, Neal; Hayward, Nicholas K.; French, Tim; Smith, Paul D.

doi:10.1158/0008-5472.can-09-1577

Cited by 278Melanoma and MAPK PathwaysProtein Kinase Regulation and GTPase SignalingProtein Tyrosine Phosphatases

Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244)

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Dry, Jonathan R., Pavey, Sandra, Pratilas, Christine A., Harbron, Chris, Runswick, Sarah, Hodgson, Darren, Chresta, Christine, McCormack, Rose +21 more·2010·Cancer Research

DOI 10.1158/0008-5472.can-09-1577PMC PMC3166660

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Abstract

Selumetinib (AZD6244, ARRY-142886) is a selective, non–ATP-competitive inhibitor of mitogen-activated protein/extracellular signal–regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR–based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies. Cancer Res; 70(6); 2264–73

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The 13-gene signature was developed from cell lines treated with MEKi for 72 h, during which adaptive resistance could be induced.
“It is noteworthy that the 13-gene signature was developed from cell lines treated with the MEKi for a 72 h period [6] during which AR could be induced [11].”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [6]
The Results (Generation of novel candidate multivariate markers) report that the authors identified a 13-gene compensatory-resistance signature. But Materials and Methods (Cell culture and cell viability assays) describes 72 hours as the period used to measure drug effects on cell growth, not as the treatment period from which the signature was developed; it describes a separate drug-treated panel exposed for 8 hours. The adaptive-resistance clause is attached to a different citation and is not assessed here. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measured
RAS/RAF-mutated CRC targeted therapies have been largely ineffective, likely due to complex resistance mechanisms such as intrinsic and adaptive resistance.
“Although RAS/RAF-mutated CRC has been targeted for the development of therapeutic inhibitors, they have been largely ineffective, likely due to complex resistance mechanisms such as intrinsic and adaptive resistance [5–12].”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [6]
The Introduction and Discussion describe MEK-targeted treatment and complex compensatory mechanisms that can make tumor cells resistant. The Results also test response in colorectal cell lines. The paper does not establish that therapies for RAS/RAF-mutated colorectal cancer have been largely ineffective clinically, or identify adaptive resistance as a cause of that broad outcome. (LLM, conf=0.85)
Experimental — accuracy not yet measured
MEK inhibitors, used alone, have been largely ineffective, likely due to intrinsic and adaptive resistance mechanisms.
“However, MEK inhibitors, used alone, have been largely ineffective, likely due to intrinsic and adaptive resistance mechanisms [5–7].”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [6]
The Discussion (page unavailable) describes resistance to MEK inhibitors through compensatory signaling, and the Results distinguish selumetinib-sensitive from resistant cell lines. The paper does not establish that MEK inhibitors used alone have been largely ineffective overall, or specifically attribute such an outcome to both intrinsic and adaptive resistance. (LLM, conf=0.83)
Experimental — accuracy not yet measured

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A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
Paik, S., Shak, S., Tang, G., Kim, C., Baker, J., Cronin, M., Baehner, F., Walker, M. G., Watson, D., Park, T., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa041588 · Cited by 6,009 · see citing works
ONCOMINE: A Cancer Microarray Database and Integrated Data-Mining Platform
Rhodes, D. R., Yu, J., Sundaram, S. K., Deshpande, N., Varambally, R., Ghosh, D., Barrette, T. R., Pander, A., & Chinnaiyan, A. M. (2004) · Neoplasia · doi:10.1016/s1476-5586(04)80047-2 · Cited by 3,615 · see citing works
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Lièvre, A., Bachet, J.-B., Le Corre, D., Boige, V., Landi, B., Emile, J.-F., Côté, J.-F., Tomasic, G., Penna, C., Ducreux, M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0191 · Cited by 2,229 · see citing works
American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer
Harris, L. N., Fritsche, H. A., Mennel, R. G., Norton, L., Ravdin, P. M., Taube, S. E., Somerfield, M. R., Hayes, D. F., & Bast, R. C. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.2364 · Cited by 2,214 · see citing works
Oncogenic pathway signatures in human cancers as a guide to targeted therapies
Bild, A., Yao, G., Chang, J. T., Wang, Q., Potti, A., Chasse, D. A. D., Joshi, M.-B., Harpole, D. H., Lancaster, J. M., Berchuck, A., et al. (2005) · Nature · doi:10.1038/nature04296 · Cited by 2,032 · see citing works
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 1,329 · see citing works
Self-citation
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 1,053 · see citing works
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 · see citing works
Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies
Stommel, J. M., Kimmelman, A. C., Ying, H., Nabioullin, R., Ponugoti, A. H., Wiedemeyer, R., Stegh, A. H., Bradner, J. E., Ligon, K. L., Brennan, C., et al. (2007) · Science · doi:10.1126/science.1142946 · Cited by 938 · see citing works
Thousands of samples are needed to generate a robust gene list for predicting outcome in cancer
Ein‐Dor, L., Zuk, O., & Domany, E. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601231103 · Cited by 691 · see citing works
Critical Review of Published Microarray Studies for Cancer Outcome and Guidelines on Statistical Analysis and Reporting
Dupuy, A., & Simon, R. M. (2007) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djk018 · Cited by 632 · see citing works
V600E BRAF is associated with disabled feedback inhibition of RAF–MEK signaling and elevated transcriptional output of the pathway
Pratilas, C. A., Taylor, B. S., Ye, Q., Viale, A. J., Sander, C., Solit, D. B., & Rosen, N. X. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900780106 · Cited by 616 · see citing works
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Liu, J., Hamrouni, A., Wołowiec, D., Coiteux, V., Kuliczkowski, K., Hétuin, D., Saudemont, A., & Quesnel, B. (2007) · Blood · doi:10.1182/blood-2006-10-051482 · Cited by 580 · see citing works
Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers
Adjei, A. A., Cohen, R. B., Franklin, W. A., Morris, C. D., Wilson, D. M., Molina, J. R., Hanson, L. J., Gore, L., Chow, L. Q. M., Leong, S., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.4956 · Cited by 568 · see citing works
PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers
Wee, S., Jagani, Z., Xiang, K. X., Loo, A., Dorsch, M., Yao, Y.-M., Sellers, W. R., Lengauer, C., & Stegmeier, F. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4765 · Cited by 455 · see citing works
Clusterin inhibits apoptosis by interacting with activated Bax
Zhang, H., Kim, J. K., Edwards, C. A., Xu, Z., Taichman, R., & Wang, C.-Y. (2005) · Nature Cell Biology · doi:10.1038/ncb1291 · Cited by 453 · see citing works
Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis
Ancrile, B., Lim, K.-H., & Counter, C. M. (2007) · Genes & Development · doi:10.1101/gad.1549407 · Cited by 422 · see citing works
Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro
Finn, R. S., Dering, J., Ginther, C., Wilson, C., Glaspy, P., Tchekmedyian, N., & Slamon, D. J. (2007) · Breast Cancer Research and Treatment · doi:10.1007/s10549-006-9463-x · Cited by 410 · see citing works
Self-citation
AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo , pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models
Davies, B. R., Logié, A., McKay, J. S., Martin, P. D., Steele, S. J., Jenkins, R., Cockerill, M. J., Cartlidge, S., & Smith, P. D. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0231 · Cited by 388 · see citing works
Self-citation
Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition
Mirzoeva, O. K., Das, D., Heiser, L. M., Bhattacharya, S., Siwak, D. R., Gendelman, R., Bayani, N., Wang, N. J., Neve, R. M., Guan, Y., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3389 · Cited by 387 · see citing works
Identification of Candidate Molecular Markers Predicting Sensitivity in Solid Tumors to Dasatinib: Rationale for Patient Selection
Huang, F., Reeves, K., Han, X., Fairchild, C., Platero, S., Wong, T. W., Lee, F., Shaw, P., & Clark, E. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3633 · Cited by 344 · see citing works
A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery
Lee, J. K., Havaleshko, D. M., Cho, H., Weinstein, J. N., Kaldjian, E. P., Karpovich, J. F., Grimshaw, A. S., & Theodorescu, D. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610292104 · Cited by 311 · see citing works
Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development
Li, C., Scott, D., Hatch, E., Tian, X.-Y., & Mansour, S. (2007) · Development · doi:10.1242/dev.02701 · Cited by 298 · see citing works
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Liu, Y., & Bodmer, W. F. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510146103 · Cited by 257 · see citing works
Genetic Predictors of MEK Dependence in Non–Small Cell Lung Cancer
Pratilas, C. A., Hanrahan, A. J., Halilovic, E., Persaud, Y., Soh, J., Chitale, D. A., Shigematsu, H., Yamamoto, H., Sawai, A., Janakiraman, M., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-2223 · Cited by 252 · see citing works
Self-citation
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Creighton, C. J., Hilger, A., Murthy, S., Rae, J. M., Chinnaiyan, A. M., & El‐Ashry, D. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4363 · Cited by 243 · see citing works
Integration of TGF-ß and Ras/MAPK Signaling Through p53 Phosphorylation
Cordenonsi, M., Montagner, M., Adorno, M., Zacchigna, L., Martello, G., Mamidi, A., Soligo, S., Dupont, S., & Piccolo, S. (2007) · Science · doi:10.1126/science.1135961 · Cited by 202 · see citing works
Microarray expression profiling in melanoma reveals a BRAF mutation signature
Pavey, S. J., Johansson, P. A., Packer, L., Taylor, J. M., Stark, M. S., Pollock, P. M., Walker, G. J., Boyle, G. M., Harper, U. L., Cozzi, S., et al. (2004) · Oncogene · doi:10.1038/sj.onc.1207563 · Cited by 193 · see citing works
Self-citation
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Yeh, J. J., Routh, E. D., Rubinas, T. C., Peacock, J., Martin, T. D., Shen, X., Sandler, R. S., Kim, H. J., Keku, T. O., & Der, C. J. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0972 · Cited by 169 · see citing works
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Papadopoulos, N., Kinzler, K. W., & Vogelstein, B. (2006) · Nature Biotechnology · doi:10.1038/nbt1234 · Cited by 147 · see citing works
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O’Hagan, R. C., Tozer, R. G., Symons, M. H., McCormick, F. P., & Hassell, J. A. (1996) · PubMed · Cited by 140 · see citing works
A Metastasis Modifier Locus on Human Chromosome 8p in Uveal Melanoma Identified by Integrative Genomic Analysis
Onken, M. D., Worley, L. A., & Harbour, J. W. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-5144 · Cited by 108 · see citing works
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Pan, K., Lih, C., & Cohen, S. N. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502674102 · Cited by 102 · see citing works
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Legrier, M., Yang, C. H., Yan, H.-G., Lopez-Barcons, L. A., Keller, S. M., Perez-Soler, R., Horwitz, S. B., & McDaid, H. M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0702 · Cited by 84 · see citing works
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Johansson, P. A., Pavey, S. J., & Hayward, N. K. (2007) · Pigment Cell Research · doi:10.1111/j.1600-0749.2007.00375.x · Cited by 84 · see citing works
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Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Initiates a Dynamic Interplay between Sumoylation and Ubiquitination To Regulate the Activity of the Transcriptional Activator PEA3
Guo, B., & Sharrocks, A. D. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01128-08 · Cited by 73 · see citing works
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Éder, K., Guan, H., Sung, H. Y., Ward, J. R., Angyal, A., Janas, M. L., Sármay, G., Duda, E., Turner, M., Dower, S., et al. (2008) · International Immunology · doi:10.1093/intimm/dxn116 · Cited by 58 · see citing works
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Kreeger, P. K., Mandhana, R., Hughes, S. K., Haigis, K. M., & Lauffenburger, D. A. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1921 · Cited by 51 · see citing works
TDAG51 is an ERK signaling target that opposes ERK-mediated HME16C mammary epithelial cell transformation
Oberst, M. D., Beberman, S. J., Liu, Z., Yin, J. J., Ward, Y., & Kelly, K. (2008) · BMC Cancer · doi:10.1186/1471-2407-8-189 · Cited by 50 · see citing works
Biomarkers in oncology drug development
Hodgson, D., Whittaker, R. D., Herath, A., Amakye, D. D., & Clack, G. (2008) · Molecular Oncology · doi:10.1016/j.molonc.2008.12.002 · Cited by 39 · see citing works
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Fenton, J. I., Lavigne, J. A., Perkins, S. N., Liu, H., Chandramouli, G. V. R., Shih, J. H., Hord, N. G., & Hursting, S. D. (2007) · Molecular Carcinogenesis · doi:10.1002/mc.20357 · Cited by 36 · see citing works
Sprouty2 Association with B-Raf Is Regulated by Phosphorylation and Kinase Conformation
Brady, S. C., Coleman, M. L., Munro, J., Feller, S. M., Morrice, N. A., & Olson, M. F. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4447 · Cited by 31 · see citing works
Take Your "M" Time
Baldassarre, G., Croce, C. M., & Vecchione, A. M. (2007) · Cell Cycle · doi:10.4161/cc.6.17.4628 · Cited by 6 · see citing works

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Systematic identification of genomic markers of drug sensitivity in cancer cells
Garnett, M. J., Edelman, E. J., Heidorn, S. J., Greenman, C. D., Dastur, A., Lau, K. W., Greninger, P., Thompson, I. R., Luo, X., Soares, J., et al. (2012) · Nature · doi:10.1038/nature11005 · Cited by 2,456 · see citing works
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Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172 · see citing works
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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 · see citing works
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Lu, Y., Zhao, X., Liu, Q., Li, C., Graves-Deal, R., Cao, Z., Singh, B., Franklin, J. L., Wang, J., Hu, H., et al. (2017) · Nature Medicine · doi:10.1038/nm.4424 · Cited by 425 · see citing works
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Saini, K. S., Loi, S., de Azambuja, E., Metzger, O., Saini, M. L., Ignatiadis, M., Dancey, J. E., & Piccart, M. J. (2013) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2013.03.009 · Cited by 376 · see citing works
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Kwong, L. N., Costello, J. C., Liu, H., Jiang, S., Helms, T. L., Langsdorf, A. E., Jakubosky, D., Genovese, G., Muller, F. L., Jeong, J. H., et al. (2012) · Nature Medicine · doi:10.1038/nm.2941 · Cited by 358 · see citing works
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MEK in cancer and cancer therapy.
Neuzillet, C., Tijeras-Raballand, A., de Mestier, L., Cros, J., Faivre, S., & Raymond, E. (2014) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2013.10.001 · Cited by 266 · see citing works
Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy
Steelman, L. S., Franklin, R. A., Abrams, S. L., Chappell, W. H., Kempf, C., Bäsecke, J., Stivala, F., Donia, M., Fagone, P., Nicoletti, F., et al. (2011) · Leukemia · doi:10.1038/leu.2011.66 · Cited by 261 · see citing works
Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines
Schlicker, A., Beran, G. J., Chresta, C. M., McWalter, G., Pritchard, A., Weston, S. L., Runswick, S. K., Davenport, S., Heathcote, K., Alférez, D., et al. (2012) · BMC Medical Genomics · doi:10.1186/1755-8794-5-66 · Cited by 253 · see citing works
Self-citation
Identification of a Poor-PrognosisBRAF-Mutant–Like Population of Patients With Colon Cancer
Popovici, V. C., Budínská, E., Tejpar, S., Weinrich, S. L., Estrella, H., Hodgson, G., Cutsem, E. V., Xie, T., Bosman, F. T., Roth, A. D., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.39.5814 · Cited by 232 · see citing works
Basal and Treatment-Induced Activation of AKT Mediates Resistance to Cell Death by AZD6244 (ARRY-142886) in Braf- Mutant Human Cutaneous Melanoma Cells
Gopal, Y. N. V., Deng, W., Woodman, S. E., Komurov, K., Ram, P. T., Smith, P. D., & Davies, M. A. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0902 · Cited by 229 · see citing works
Self-citation
Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial
Lee, J., Kim, S. T., Kim, K., Lee, H., Kozarewa, I., Mortimer, P. G. S., Odegaard, J. I., Harrington, E. A., Lee, J.-Y., Lee, T., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0442 · Cited by 230 · see citing works
PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types
Britten, C. D. (2013) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-013-2121-1 · Cited by 216 · see citing works
Amplification of the Driving Oncogene, KRAS or BRAF , Underpins Acquired Resistance to MEK1/2 Inhibitors in Colorectal Cancer Cells
Little, A. S., Balmanno, K., Sale, M. J., Newman, S., Dry, J. R., Hampson, M., Edwards, P. A., Smith, P. D., & Cook, S. J. (2011) · Science Signaling · doi:10.1126/scisignal.2001752 · Cited by 211 · see citing works
Self-citation
A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC
Schell, M. J., Yang, M., Teer, J. K., Lo, F. Y., Madan, A., Coppola, D., Monteiro, A. N. A., Nebozhyn, M. V., Yue, B., Loboda, A., et al. (2016) · Nature Communications · doi:10.1038/ncomms11743 · Cited by 207 · see citing works
A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types
Wagle, M.-C., Kirouac, D. C., Klijn, C. N., Liu, B., Mahajan, S., Junttila, M. R., Moffat, J. G., Merchant, M. A., Huw, L. Y., Wongchenko, M. J., et al. (2018) · npj Precision Oncology · doi:10.1038/s41698-018-0051-4 · Cited by 189 · see citing works
Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS
Ross, S. J., Revenko, A. S., Hanson, L. L., Ellston, R., Staniszewska, A., Whalley, N., Pandey, S. K., Revill, M., Rooney, C., Buckett, L. K., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aal5253 · Cited by 177 · see citing works
Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways
McCubrey, J. A., Steelman, L. S., Kempf, C., Chappell, W. H., Abrams, S. L., Stivala, F., Malaponte, G., Nicoletti, F., Libra, M., Bäsecke, J., et al. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22647 · Cited by 173 · see citing works
New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome
Wilson, L., Linley, A. J., Hammond, D. E., Hood, F. E., Coulson, J. M., MacEwan, D. J., Ross, S. J., Slupsky, J. R., Smith, P. D., Eyers, P. A., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-2291 · Cited by 171 · see citing works
Self-citation
Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas
Way, G. P., Sánchez-Vega, F., La, K., Armenia, J., Chatila, W. K., Luna, A., Sander, C., Cherniack, A. D., Mina, M., Ciriello, G., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.046 · Cited by 166 · see citing works
Self-citation
Advances in the preclinical testing of cancer therapeutic hypotheses
Caponigro, G., & Sellers, W. R. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3385 · Cited by 165 · see citing works
Analysis of the genome to personalize therapy for melanoma
Davies, M. A., & Samuels, Y. (2010) · Oncogene · doi:10.1038/onc.2010.323 · Cited by 167 · see citing works
MAPK pathway activity plays a key role in PD‐L1 expression of lung adenocarcinoma cells
Stutvoet, T. S., Kol, A., de Vries, E. G. E., de Bruyn, M., Fehrmann, R. S. N., van Scheltinga, A. G. T. T., & de Jong, S. (2019) · The Journal of Pathology · doi:10.1002/path.5280 · Cited by 162 · see citing works
Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors
Sommer, E. M., Dry, H., Cross, D. A. E., Guichard, S. M., Davies, B. R., & Alessi, D. R. (2013) · Biochemical Journal · doi:10.1042/bj20130342 · Cited by 158 · see citing works
Wnt/β-Catenin Signaling and AXIN1 Regulate Apoptosis Triggered by Inhibition of the Mutant Kinase BRAF V600E in Human Melanoma
Biechele, T. L., Kulikauskas, R. M., Toroni, R. A., Lucero, O. M., Swift, R. D., James, R. G., Robin, N. C., Dawson, D. W., Moon, R. T., & Chien, A. J. (2012) · Science Signaling · doi:10.1126/scisignal.2002274 · Cited by 158 · see citing works
KRAS Mutation and Consensus Molecular Subtypes 2 and 3 Are Independently Associated with Reduced Immune Infiltration and Reactivity in Colorectal Cancer
Lal, N., White, B. S., Goussous, G., Pickles, O. J., Mason, M. J., Beggs, A. D., Tanière, P., Willcox, B. E., Guinney, J., & Middleton, G. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1090 · Cited by 154 · see citing works
MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma
Yohe, M. E., Gryder, B. E., Shern, J. F., Song, Y., Chou, H.-C., Sindiri, S., Mendoza, A., Patidar, R., Zhang, X., Guha, R., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan4470 · Cited by 148 · see citing works
KRAS-G12C Mutation Is Associated with Poor Outcome in Surgically Resected Lung Adenocarcinoma
Nadal, E., Chen, G., Prensner, J. R., Shiratsuchi, H., Sam, C., Zhao, L., Kalemkerian, G. P., Brenner, D. E., Lin, J., Reddy, R. M., et al. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000305 · Cited by 139 · see citing works
Artificial Intelligence in Pharmaceutical Sciences
Lu, M., Yin, J., Zhu, Q., Lin, G., Mou, M., Liu, F., Pan, Z., You, N., Lian, X., Li, F., et al. (2023) · Engineering · doi:10.1016/j.eng.2023.01.014 · Cited by 139 · see citing works
KRAS Mutations as Prognostic and Predictive Markers in Non–Small Cell Lung Cancer
Martin, P., Leighl, N. B., Tsao, M., & Shepherd, F. A. (2013) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318283d958 · Cited by 134 · see citing works
Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer
Li, S., Fong, K.-W., Gritsina, G., Zhang, A., Zhao, J. C., Kim, J., Sharp, A., Yuan, W., Aversa, C., Yang, X. J., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2812 · Cited by 128 · see citing works
A combined oncogenic pathway signature of BRAF , KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction
Tian, S., Simon, I., Moreno, V., Roepman, P., Tabernero, J., Snel, M., van't Veer, L., Salazar, R., Bernards, R., & Capella, G. (2013) · Gut · doi:10.1136/gutjnl-2012-302423 · Cited by 128 · see citing works
Comprehensive Predictive Biomarker Analysis for MEK Inhibitor GSK1120212
Jing, J., Greshock, J. D., Holbrook, J. D., Gilmartin, A. G., Zhang, X., McNeil, E., Conway, T. M., Moy, C. H., Laquerre, S. G., Bachman, K., et al. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0505 · Cited by 121 · see citing works
Identification of Unique MEK-Dependent Genes in GNAQ Mutant Uveal Melanoma Involved in Cell Growth, Tumor Cell Invasion, and MEK Resistance
Ambrosini, G., Pratilas, C. A., Qin, L., Tadi, M., Surriga, O., Carvajal, R. D., & Schwartz, G. K. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-3086 · Cited by 110 · see citing works
Self-citation
EGFR-targeted therapy
Vecchione, L., Jacobs, B., Normanno, N., Ciardiello, F., & Tejpar, S. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.08.021 · Cited by 107 · see citing works
MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines
Vultur, A., Villanueva, J., Krepler, C., Rajan, G., Chen, Q., Xiao, M., Li, L., Gimotty, P. A., Wilson, M. A., Hayden, J., et al. (2013) · Oncogene · doi:10.1038/onc.2013.131 · Cited by 100 · see citing works
The IL-6 feed-forward loop: A driver of tumorigenesis
Chang, Q., Daly, L., & Bromberg, J. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.01.007 · Cited by 99 · see citing works
STAT3 Mediates Resistance to MEK Inhibitor through MicroRNA miR-17
Dai, B., Meng, J., Peyton, M., Girard, L., Bornmann, W. G., Ji, L., Minna, J. D., Fang, B., & Roth, J. A. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-3647 · Cited by 95 · see citing works
Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi‐targeted kinase inhibitors in pimasertib‐resistant human lung and colorectal cancer cells
Martinelli, E., Troiani, T., D'Aiuto, E., Morgillo, F., Vitagliano, D., Capasso, A., Costantino, S., Ciuffreda, L. P., Merolla, F., Vecchione, L., et al. (2013) · International Journal of Cancer · doi:10.1002/ijc.28236 · Cited by 92 · see citing works
Acquired Resistance to BRAF Inhibition Can Confer Cross-Resistance to Combined BRAF/MEK Inhibition
Gowrishankar, K., Snoyman, S., Pupo, G. M., Becker, T. M., Kefford, R. F., & Rizos, H. (2012) · Journal of Investigative Dermatology · doi:10.1038/jid.2012.63 · Cited by 90 · see citing works
Deep generative neural network for accurate drug response imputation
Jia, P., Hu, R., Pei, G., Dai, Y., Wang, Y., & Zhao, Z. (2021) · Nature Communications · doi:10.1038/s41467-021-21997-5 · Cited by 89 · see citing works
Activation and Involvement of Ral GTPases in Colorectal Cancer
Martin, T. D., Samuel, J. C., Routh, E. D., Der, C. J., & Yeh, J. J. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-1517 · Cited by 88 · see citing works
Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)
Holt, S. V., Logié, A., Davies, B. R., Alférez, D., Runswick, S. K., Fenton, S. E., Chresta, C. M., Gu, Y., Zhang, J., Wu, Y.-L. L. C., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-1780 · Cited by 86 · see citing works
Self-citation
Cortactin Phosphorylated by ERK1/2 Localizes to Sites of Dynamic Actin Regulation and Is Required for Carcinoma Lamellipodia Persistence
Kelley, L. C., Hayes, K. E., Ammer, A. G., Martin, K. H., & Weed, S. A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013847 · Cited by 85 · see citing works
Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C
Kettle, J. G., Bagal, S. K., Bickerton, S., Bodnarchuk, M. S., Breed, J., Carbajo, R. J., Cassar, D. J., Chakraborty, A., Cosulich, S. C., Cumming, I. A., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01720 · Cited by 85 · see citing works
A double-negative feedback loop between EpCAM and ERK contributes to the regulation of epithelial–mesenchymal transition in cancer
Sankpal, N. V., Fleming, T. P., Sharma, P. K., Wiedner, H. J., & Gillanders, W. E. (2017) · Oncogene · doi:10.1038/onc.2016.504 · Cited by 81 · see citing works
Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models
Tan, N., Wong, M., Nannini, M., Hong, R., Lee, L. B., Price, S., Williams, K. R., Savy, P., Yue, P., Sampath, D., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0949 · Cited by 79 · see citing works
Transcriptomic Determinants of Response to Pembrolizumab Monotherapy across Solid Tumor Types
Cristescu, R., Nebozhyn, M., Zhang, C., Albright, A. V., Kobie, J., Huang, L., Zhao, Q., Wang, A., Ma, H., Cao, Z. A., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-3329 · Cited by 80 · see citing works
Identification of Predictive Markers of Response to the MEK1/2 Inhibitor Selumetinib (AZD6244) in K- ras –Mutated Colorectal Cancer
Tentler, J. J., Nallapareddy, S., Tan, A. C., Spreafico, A., Pitts, T. M., Morelli, M. P., Selby, H. M., Kachaeva, M. I., Flanigan, S. A., Kulikowski, G. N., et al. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-10-0376 · Cited by 77 · see citing works
Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C
Kettle, J. G., Bagal, S. K., Bickerton, S., Bodnarchuk, M. S., Boyd, S., Breed, J., Carbajo, R. J., Cassar, D. J., Chakraborty, A., Cosulich, S. C., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00369 · Cited by 69 · see citing works
Phosphoproteomic Analysis of Leukemia Cells under Basal and Drug-treated Conditions Identifies Markers of Kinase Pathway Activation and Mechanisms of Resistance
Alcolea, M. P., Casado, P., Rodríguez‐Prados, J., Vanhaesebroeck, B., & Cutillas, P. R. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m112.017483 · Cited by 69 · see citing works
Combination of pan-RAF and MEK inhibitors in NRAS mutant melanoma
Atefi, M., Titz, B., Avramis, E. V., Ng, C., Wong, D., Lassen, A., Cerniglia, M., Escuin-Ordinas, H., Foulad, D., Comin-Anduix, B., et al. (2015) · Molecular Cancer · doi:10.1186/s12943-015-0293-5 · Cited by 65 · see citing works
Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines
Cursons, J., Leuchowius, K., Waltham, M. C., Tomaskovic‐Crook, E., Foroutan, M., Bracken, C. P., Redfern, A. D., Crampin, E. J., Street, I. P., Davis, M. J., et al. (2015) · Cell Communication and Signaling · doi:10.1186/s12964-015-0106-x · Cited by 65 · see citing works
Targeting the KRAS variant for treatment of non-small cell lung cancer: potential therapeutic applications
Ricciuti, B., Leonardi, G. C., Metro, G., Grignani, F., Paglialunga, L., Bellezza, G., Baglivo, S., Mencaroni, C., Baldi, A., Zicari, D., et al. (2015) · Expert Review of Respiratory Medicine · doi:10.1586/17476348.2016.1115349 · Cited by 65 · see citing works
The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets
Rocca, A., Braga, L., Volpe, M. C., Maiocchi, S., & Generali, D. (2022) · Cancers · doi:10.3390/cancers14215306 · Cited by 65 · see citing works
Rational Combination of a MEK Inhibitor, Selumetinib, and the Wnt/Calcium Pathway Modulator, Cyclosporin A, in Preclinical Models of Colorectal Cancer
Spreafico, A., Tentler, J. J., Pitts, T. M., Tan, A. C., Gregory, M. A., Arcaroli, J. J., Klauck, P. J., McManus, M. C., Hansen, R. J., Kim, J., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3140 · Cited by 64 · see citing works
Identification of Common Predictive Markers of In vitro Response to the Mek Inhibitor Selumetinib (AZD6244; ARRY-142886) in Human Breast Cancer and Non–Small Cell Lung Cancer Cell Lines
Garon, E. B., Finn, R. S., Hosmer, W., Dering, J., Ginther, C., Adhami, S., Kamranpour, N., Pitts, S. L., Desai, A. J., Elashoff, D. A., et al. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-10-0037 · Cited by 63 · see citing works
Self-citation
Low-grade serous carcinoma: New concepts and emerging therapies
Romero, I., Sun, C. C., Wong, K., Bast, R. C., & Gershenson, D. M. (2013) · Gynecologic Oncology · doi:10.1016/j.ygyno.2013.05.021 · Cited by 63 · see citing works
BRAF -Mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer
Middleton, G., Yang, Y., Campbell, C. D., André, T., Atreya, C. E., Schellens, J. H. M., Yoshino, T., Bendell, J. C., Hollebecque, A., McRee, A. J., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3579 · Cited by 63 · see citing works
RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors
Su, Y., Vilgelm, A. E., Kelley, M. C., Hawkins, O. E., Liu, Y., Boyd, K. L., Kantrow, S. M., Splittgerber, R. C., Short, S. P., Sobolik, T., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1122 · Cited by 62 · see citing works
MEK inhibitors as a chemotherapeutic intervention in multiple myeloma
Leow, C. C.-Y., Gerondakis, S., & Spencer, A. (2013) · Blood Cancer Journal · doi:10.1038/bcj.2013.1 · Cited by 61 · see citing works
Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation
Yang, Q., Huo, Y., Han, Y., Lili, W., Li, J., Huang, J., Jin, L., Peng-Guo, C., Gan, R., & Guo, C. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0324 · Cited by 60 · see citing works
BRAF mutations are associated with increased iron regulatory protein‐2 expression in colorectal tumorigenesis
Horniblow, R. D., Bedford, M., Hollingworth, R., Evans, S. C., Sutton, E., Lal, N., Beggs, A. D., Iqbal, T. H., & Tselepis, C. (2017) · Cancer Science · doi:10.1111/cas.13234 · Cited by 60 · see citing works
Development, Characterization, and Reversal of Acquired Resistance to the MEK1 Inhibitor Selumetinib (AZD6244) in an In Vivo Model of Childhood Astrocytoma
Bid, H. K., Kibler, A., Phelps, D. A., Manap, S., Xiao, L., Lin, J., Capper, D., Oswald, D. J., Geier, B., DeWire, M. D., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0842 · Cited by 59 · see citing works
Self-citation
SPRED proteins and their roles in signal transduction, development, and malignancyPreprint
Lorenzo, C., & McCormick, F. P. (2020) · Genes & Development · doi:10.1101/gad.341222.120 · Cited by 59 · see citing works
The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells
Criscione, S. W., Martin, M. J., Oien, D. B., Gorthi, A., Miragaia, R. J., Zhang, J., Chen, H., Karl, D. L., Mendler, K., Markovets, A. A., et al. (2022) · npj Precision Oncology · doi:10.1038/s41698-022-00337-w · Cited by 55 · see citing works
Self-citation
Evaluation of the In Vitro and In Vivo Efficacy of the JAK Inhibitor AZD1480 against JAK-Mutated Acute Lymphoblastic Leukemia
Suryani, S., Bracken, L. S., Harvey, R. C., Sia, K. C. S., Carol, H., Chen, I., Evans, K., Dietrich, P. A., Roberts, K. G., Kurmasheva, R. T., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0647 · Cited by 57 · see citing works
Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies
Igoe, N., Bayle, E. D., Fedorov, O., Tallant, C., Savitsky, P. A., Rogers, C. M., Owen, D. R., Deb, G., Somervaille, T. C. P., Andrews, D. M., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01583 · Cited by 56 · see citing works
RAS–MAPK Pathway-Driven Tumor Progression Is Associated with Loss of CIC and Other Genomic Aberrations in Neuroblastoma
Eleveld, T. F., Schild, L. G., Köster, J., Zwijnenburg, D. A., Alles, L. K., Ebus, M. E., Volckmann, R., Tijtgat, G. A., Sluis, P. V., Versteeg, R., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-1045 · Cited by 55 · see citing works
COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors
Xie, Y., Cao, Z., Wong, E. W. P., Guan, Y., Ma, W., Zhang, J. Q., Walczak, E. G., Murphy, D. A., Ran, L., Sirota, I., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci94840 · Cited by 51 · see citing works
MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance
Sale, M. J., Balmanno, K., Saxena, J., Ozono, E., Wojdyła, K., McIntyre, R. E., Gilley, R., Woroniuk, A., Howarth, K., Hughes, G. D., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09438-w · Cited by 52 · see citing works
Self-citation
HER2+ Cancer Cell Dependence on PI3K vs. MAPK Signaling Axes Is Determined by Expression of EGFR, ERBB3 and CDKN1B
Kirouac, D. C., Du, J., Lahdenranta, J., Onsum, M. D., Nielsen, U. B., Schoeberl, B., & McDonagh, C. F. (2016) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004827 · Cited by 49 · see citing works
Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer
Wang, C., Wang, H., Zheng, C., Liu, Z., Gao, X., Xu, F., Niu, Y., Zhang, L., & Xu, P. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113386 · Cited by 49 · see citing works
Consistency in large pharmacogenomic studies
Geeleher, P., Gamazon, E. R., Seoighe, C., Cox, N. J., & Huang, R. S. (2016) · Nature · doi:10.1038/nature19838 · Cited by 46 · see citing works
Preclinical Activity of the Rational Combination of Selumetinib (AZD6244) in Combination with Vorinostat in KRAS-Mutant Colorectal Cancer Models
Morelli, M. P., Tentler, J. J., Kulikowski, G. N., Tan, A. C., Bradshaw‐Pierce, E. L., Pitts, T. M., Brown, A. M., Nallapareddy, S., Arcaroli, J. J., Serkova, N. J., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1507 · Cited by 47 · see citing works
Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells
Troiani, T., Vecchione, L., Martinelli, E., Capasso, A., Costantino, S., Ciuffreda, L. P., Morgillo, F., Vitagliano, D., D’Aiuto, E., Palma, R. D., et al. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.129 · Cited by 46 · see citing works
Systems analysis identifies potential target genes to overcome cetuximab resistance in colorectal cancer cells
Park, S., Hwang, C. Y., Cho, S., Lee, D., Gong, J., Lee, S., Nam, S., & Cho, K. (2019) · FEBS Journal · doi:10.1111/febs.14773 · Cited by 46 · see citing works
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East, P., Kelly, G. P., Biswas, D., Marani, M., Hancock, D. C., Creasy, T. H., Sachsenmeier, K. F., Swanton, C., Downward, J., & Trécesson, S. D. C. (2022) · Nature Communications · doi:10.1038/s41467-022-33290-0 · Cited by 42 · see citing works
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Schell, M. J., Yang, M., Missiaglia, E., Delorenzi, M., Soneson, C., Yue, B., Nebozhyn, M. V., Loboda, A., Bloom, G., & Yeatman, T. J. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0143 · Cited by 42 · see citing works
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Vogel, C., Smit, M. A., Maddalo, G., Possik, P. A., Sparidans, R. W., van der Burg, S. H., Verdegaal, E. M. E., Heck, A. J. R., Samatar, A. A., Beijnen, J. H., et al. (2015) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12364 · Cited by 44 · see citing works
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Ricciardi, M. R., Scerpa, M. C., Bergamo, P., Ciuffreda, L., Petrucci, M. T., Chiaretti, S., Tavolaro, S., Mascolo, M. G., Abrams, S. L., Steelman, L. S., et al. (2012) · Journal of Molecular Medicine · doi:10.1007/s00109-012-0886-z · Cited by 43 · see citing works
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Maiello, M. R., D’Alessio, A., Bevilacqua, S., Gallo, M., Normanno, N., & Luca, A. D. (2015) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25220 · Cited by 42 · see citing works
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Kim, R. D., McDonough, S. L., El-Khoueiry, A. B., Bekaii‐Saab, T., Stein, S., Sahai, V., Keogh, G. P., Kim, E. J.-H., Baron, A. D., Siegel, A. B., et al. (2020) · European Journal of Cancer · doi:10.1016/j.ejca.2020.01.026 · Cited by 42 · see citing works
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Igoe, N., Bayle, E. D., Tallant, C., Fedorov, O., Meier, J. C., Savitsky, P. A., Rogers, C. M., Morias, Y., Scholze, S., Boyd, H., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00611 · Cited by 41 · see citing works
Distribution of KRAS, DDR2, and TP53 gene mutations in lung cancer: An analysis of Iranian patients
Fathi, Z., Mousavi, S. A., Roudi, R., & Ghazi, F. (2018) · PLoS ONE · doi:10.1371/journal.pone.0200633 · Cited by 40 · see citing works
MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas
Sigaud, R., Albert, T., Hess, C. C., Hielscher, T., Winkler, N., Kocher, D., Walter, C., Münter, D., Selt, F., Usta, D., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40235-8 · Cited by 39 · see citing works
Looking beyond the cancer cell for effective drug combinations
Dry, J. R., Yang, M., & Sáez-Rodríguez, J. (2016) · Genome Medicine · doi:10.1186/s13073-016-0379-8 · Cited by 39 · see citing works
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Fang, Y., Xu, P., Yang, J., & Qin, Y. (2018) · PLoS ONE · doi:10.1371/journal.pone.0205155 · Cited by 39 · see citing works
Combination MEK and mTOR inhibitor therapy is active in models of glioblastoma
Schreck, K. C., Allen, A. N., Wang, J., & Pratilas, C. A. (2020) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdaa138 · Cited by 39 · see citing works
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Kettle, J. G., Bagal, S. K., Barratt, D. G., Bodnarchuk, M. S., Boyd, S., Braybrooke, E. L., Breed, J., Cassar, D. J., Cosulich, S. C., Davies, M., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00746 · Cited by 38 · see citing works

Identification of Common Predictive Markers of In vitro Response to the Mek Inhibitor Selumetinib (AZD6244; ARRY-142886) in Human Breast Cancer and Non–Small Cell Lung Cancer Cell Lines
Garon, E. B., Finn, R. S., Hosmer, W., Dering, J., Ginther, C., Adhami, S., Kamranpour, N., Pitts, S. L., Desai, A. J., Elashoff, D. A., et al. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-10-0037 · Cited by 63 · see citing works
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Abstract A209: Predicting genetic drivers of MEK dependency with gene expression.
Dry, J. R., Hodgson, D., Brant, R., Liptrot, T., Harrington, E. A., Barrett, C. J., & Smith, P. D. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.targ-13-a209
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Biologically driven interpretation reveals molecular signatures predictive of oncogenic addiction to MEK signaling and cell line response to the MEK1/2 inhibitor AZD6244 (ARRY-142886)
Dry, J. R., Harbron, C. G., Hickinson, M. D., Graham, A., French, T., Chang, K., Cassidy, A., Beran, G. J., Cockerill, M. J., Chresta, C. M., et al. (2008) · Cancer Research · Cited by 1 · see citing works
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Identification of Predictive Markers of Response to the MEK1/2 Inhibitor Selumetinib (AZD6244) in K- ras –Mutated Colorectal Cancer
Tentler, J. J., Nallapareddy, S., Tan, A. C., Spreafico, A., Pitts, T. M., Morelli, M. P., Selby, H. M., Kachaeva, M. I., Flanigan, S. A., Kulikowski, G. N., et al. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-10-0376 · Cited by 77 · see citing works
Abstract 2284: Phase II trial of MEK inhibitor selumetinib (AZD6244) in patients with BRAFV600E/K- or NRAS-mutated melanoma.
Catalanotti, F., Solit, D. B., Pulitzer, M. P., Berger, M. F., Scott, S. N., Iyriboz, T. A., Lacouture, M. E., Panageas, K. S., Wolchok, J. D., Carvajal, R. D., et al. (2013) · Cancer Research · doi:10.1158/1538-7445.am2013-2284
Self-citation

Authors: Dry, J. R., Pavey, S., Pratilas, C. A., Harbron, C., Runswick, S., Hodgson, D., Chresta, C., McCormack, R., Byrne, N., Cockerill, M., Graham, A., Beran, G., Cassidy, A., Haggerty, C., Brown, H., Ellison, G., Dering, J., Taylor, B. S., Stark, M., Bonazzi, V., Ravishankar, S., Packer, L., Xing, F., Solit, D. B., Finn, R. S., Rosen, N., Hayward, N. K., French, T., & Smith, P. D.
Affiliations: AstraZeneca (United Kingdom) (GB)
Corresponding author: Dry, Jonathan R.
ORCID: Dry, Jonathan R.
Pavey, Sandra
Pratilas, Christine A.
Harbron, Chris
Runswick, Sarah
Hodgson, Darren
Cassidy, Andrew
Brown, Helen
Taylor, Barry S.
Stark, Mitchell
Bonazzi, Vanessa
Xing, Feng
Solit, David B.
Finn, Richard S.
Rosen, Neal
Hayward, Nicholas K.
French, Tim
Smith, Paul D.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2010-03-14
Volume: 70
Issue: 6
Pages: 2264-2273
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-09-1577
PMC: PMC3166660
OpenAlex: W2128445526
Cited by: 262
References: 46
Citations by year: 2026: 7 · 2025: 11 · 2024: 11 · 2023: 23 · 2022: 13 · 2021: 11 · 2020: 11 · 2019: 17 · 2018: 16 · 2017: 22 · 2016: 17 · 2015: 14 · 2014: 16 · 2013: 23 · 2012: 23
FWCI: 9.50
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (K08CA127350)
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: selumetinib, MEK inhibitors, drug resistance, gene expression signatures, phosphatidylinositol 3-kinase, melanoma, cancer cell lines, xenograft models, predictive biomarkers, targeted therapy
MeSH terms: Benzimidazoles, Humans, Neoplasms, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase

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Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244)

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