ArticleMolecular cancer therapeutics2010
Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer.
Article in Molecular cancer therapeutics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 74 citations in OpenAlex.
- Pooled it
- A pH-responsive silver nanoparticle platform overcomes MEK inhibitor resistance in neurofibroma via triacsin C-mediated lipid metabolic reprogramming.Apoptosis : an international journal on programmed cell death · 2026Article
- Wnt signaling in colorectal cancer: pathogenic role and therapeutic target.Molecular cancer · 2022Review
- Small-Molecule RAS Inhibitors as Anticancer Agents: Discovery, Development, and Mechanistic Studies.International journal of molecular sciences · 2022Review
- Current methods in translational cancer research.Cancer metastasis reviews · 2021Review
- Biomarkers in Colorectal Cancer: Current Research and Future Prospects.International journal of molecular sciences · 2020Review
- RUNX2/CBFB modulates the response to MEK inhibitors through activation of receptor tyrosine kinases in KRAS-mutant colorectal cancer.Translational oncology · 2020Article
- Zebrafish Avatars towards Personalized Medicine-A Comparative Review between Avatar Models.Cells · 2020Review
- Overactivation of Akt Contributes to MEK Inhibitor Primary and Acquired Resistance in Colorectal Cancer Cells.Cancers · 2019Article
- Cyclosporine A sensitizes lung cancer cells to crizotinib through inhibition of the Ca2EBioMedicine · 2019Article
- Targeting β-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations.British journal of cancer · 2019Article
- Colorectal Cancer Biomarkers in the Era of Personalized Medicine.Journal of personalized medicine · 2019Review
- Phase Ib Results of the Rational Combination of Selumetinib and Cyclosporin A in Advanced Solid Tumors with an Expansion Cohort in Metastatic Colorectal Cancer.Cancer research · 2018Article
- Targeting HPV16 DNA using CRISPR/Cas inhibits anal cancer growthFuture virology · 2018Article
- Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer.BMC cancer · 2018Article
- β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models.Molecular cancer therapeutics · 2018Article
- Exercise inhibits tumor growth and central carbon metabolism in patient-derived xenograft models of colorectal cancer.Cancer & metabolism · 2018Article
- Evaluation of TAK-264, an Antibody-Drug Conjugate in Pancreatic Cancer Cell Lines and Patient-Derived Xenograft Models.Clinical cancer drugs · 2018Article
- Ex vivo treatment of patient biopsies as a novel method to assess colorectal tumour response to the MEK1/2 inhibitor, Selumetinib.Scientific reports · 2017Article
- Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
Mutant K-ras activity leads to the activation of the RAS/RAF/MEK/ERK pathway in approximately 44% of colorectal cancer (CRC) tumors. Accordingly, several inhibitors of the MEK pathway are under clinical evaluation in several malignancies including CRC. The aim of this study was to develop and characterize predictive biomarkers of response to the MEK1/2 inhibitor AZD6244 in CRC in order to maximize the clinical utility of this agent. Twenty-seven human CRC cell lines were exposed to AZD6244 and classified according to the IC(50) value as sensitive (≤ 0.1 μmol/L) or resistant (>1 μmol/L). All cell lines were subjected to immunoblotting for effector proteins, K-ras/BRAF mutation status, and baseline gene array analysis. Further testing was done in cell line xenografts and K-ras mutant CRC human explants models to develop a predictive genomic classifier for AZD6244. The most sensitive and resistant cell lines were subjected to differential gene array and pathway analyses. Members of the Wnt signaling pathway were highly overexpressed in cell lines resistant to AZD6244 and seem to be functionally involved in mediating resistance by shRNA knockdown studies. Baseline gene array data from CRC cell lines and xenografts were used to develop a k-top scoring pair (k-TSP) classifier, which predicted with 71% accuracy which of a test set of patient-derived K-ras mutant CRC explants would respond to AZD6244, providing the basis for a patient-selective clinical trial. These results also indicate that resistance to AZD6244 may be mediated, in part, by the upregulation of the Wnt pathway, suggesting potential rational combination partners for AZD6244 in CRC.
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