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Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244)
Open accessPublished version of a preprint
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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“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]
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“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]
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“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]
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Gene expression profiling predicts clinical outcome of breast cancer
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A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer
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KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer
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
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BRAF mutation predicts sensitivity to MEK inhibition
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Self-citationBRAF 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
Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies
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Metadata
- 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
- Venue
- Cancer Research
- Published
- 2010-03-14
- Volume
- 70
- Issue
- 6
- Pages
- 2264-2273
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- 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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