Abstract
Cellular signaling pathways involving mTOR, PI3K and ERK have dominated recent studies of breast cancer biology, and inhibitors of these pathways have formed a focus of numerous clinical trials. We have chosen trametinib, a drug targeting MEK in the ERK pathway, to address two questions. Firstly, does inhibition of a signaling pathway, as measured by protein phosphorylation, predict the antiproliferative activity of trametinib? Secondly, do inhibitors of the mTOR and PI3K pathways synergize with trametinib in their effects on cell proliferation? A panel of 30 human breast cancer cell lines was chosen to include lines that could be classified according to whether they were ER and PR positive, HER2 over-expressing, and "triple negative". Everolimus (targeting mTOR), NVP-BEZ235 and GSK2126458 (both targeting PI3K/mTOR) were chosen for combination experiments. Inhibition of cell proliferation was measured by IC50 values and pathway utilization was measured by phosphorylation of signaling kinases. Overall, no correlation was found between trametinib IC50 values and inhibition of ERK signaling. Inhibition of ERK phosphorylation was observed at trametinib concentrations not affecting proliferation, and sensitivity of cell proliferation to trametinib was found in cell lines with low ERK phosphorylation. Evidence was found for synergy between trametinib and either everolimus, NVP-BEZ235 or GSK2126458, but this was cell line specific. The results have implications for the clinical application of PI3K/mTOR and MEK inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Blotting, Western
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Drug Synergism
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Everolimus
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Humans
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Imidazoles / pharmacology
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Inhibitory Concentration 50
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MAP Kinase Signaling System / drug effects
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MCF-7 Cells
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Pyridazines
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Pyridones / pharmacology*
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Pyrimidinones / pharmacology*
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Quinolines / pharmacology
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Signal Transduction / drug effects*
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Sirolimus / analogs & derivatives
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Sirolimus / pharmacology
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Sulfonamides / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism
Substances
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Antineoplastic Agents
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Imidazoles
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Phosphoinositide-3 Kinase Inhibitors
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Pyridazines
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Pyridones
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Pyrimidinones
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Quinolines
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Sulfonamides
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omipalisib
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trametinib
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Everolimus
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MTOR protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Extracellular Signal-Regulated MAP Kinases
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dactolisib
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Sirolimus
Grants and funding
Funding for this work was obtained from the New Zealand Breast Cancer Foundation, the Maurice and Phyllis Paykel trust, Auckland Medical Research Foundation, and the Robert McClelland Trust. This work is also supported by Auckland Cancer Society Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.