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

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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, 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.·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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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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