ArticleClinical cancer research : an official journal of the American Association for Cancer Research2013
Rational combination of a MEK inhibitor, selumetinib, and the Wnt/calcium pathway modulator, cyclosporin A, in preclinical models of colorectal cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 64 citations in OpenAlex.
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- Biomarkers in Colorectal Cancer: Current Research and Future Prospects.International journal of molecular sciences · 2020Review
- Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways.Bioscience reports · 2020Review
- Drug screening in Drosophila; why, when, and when not?Wiley interdisciplinary reviews. Developmental biology · 2019Review
- Synergistic inhibition of MEK and reciprocal feedback networks for targeted intervention in malignancy.Cancer biology & medicine · 2019Article
- Cyclosporine A sensitizes lung cancer cells to crizotinib through inhibition of the Ca2EBioMedicine · 2019Article
- Colorectal Cancer Biomarkers in the Era of Personalized Medicine.Journal of personalized medicine · 2019Review
- Synergy from gene expression and network mining (SynGeNet) method predicts synergistic drug combinations for diverse melanoma genomic subtypes.NPJ systems biology and applications · 2019Article
- 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
- Emerging Systemic Therapies for Colorectal Cancer.Clinics in colon and rectal surgery · 2018Review
- 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
- Patient-derived xenograft in zebrafish embryos: a new platform for translational research in gastric cancer.Journal of experimental & clinical cancer research : CR · 2017Article
- Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of Trametinib and Dabrafenib.Oncotarget · 2017Article
- Article
- The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Article
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 1 country.
Funding
Abstract
purposeThe mitogen-activated protein kinase (MAPK) pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. MEK inhibitors are being explored as a treatment option for patients with KRAS-mutant colorectal cancer who are not candidates for EGFR-directed therapies. Initial clinical results of MEK inhibitors have yielded limited single-agent activity in colorectal cancer, indicating that rational combination strategies are needed. EXPERIMENTAL
designIn this study, we conducted unbiased gene set enrichment analysis and synthetic lethality screens with selumetinib, which identified the noncanonical Wnt/Ca++ signaling pathway as a potential mediator of resistance to the MEK1/2 inhibitor selumetinib. To test this, we used shRNA constructs against relevant WNT receptors and ligands resulting in increased responsiveness to selumetinib in colorectal cancer cell lines. Further, we evaluated the rational combination of selumetinib and WNT pathway modulators and showed synergistic antiproliferative effects in in vitro and in vivo models of colorectal cancer.
resultsImportantly, this combination not only showed tumor growth inhibition but also tumor regression in the more clinically relevant patient-derived tumor explant (PDTX) models of colorectal cancer. In mechanistic studies, we observed a trend toward increased markers of apoptosis in response to the combination of MEK and WntCa(++) inhibitors, which may explain the observed synergistic antitumor effects.
conclusionsThese results strengthen the hypothesis that targeting both the MEK and Wnt pathways may be a clinically effective rational combination strategy for patients with metastatic colorectal cancer.
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