Oncogene, 2015-08, Vol.34 (32), p.4199-4210
2015
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- Autor(en) / Beteiligte
- Titel
- A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells
- Ist Teil von
- Oncogene, 2015-08, Vol.34 (32), p.4199-4210
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Antiestrogen resistance is a major problem in breast cancer treatment. Therefore, the search for new therapeutic targets and biomarkers for antiestrogen resistance is crucial. In this study, we performed a kinase inhibitor screen on antiestrogen responsive MCF-7 cells and a panel of MCF-7-derived tamoxifen- and fulvestrant-resistant cell lines. Our focus was to identify common and distinct molecular mechanisms involved in tamoxifen- and fulvestrant-resistant cell growth. We identified 18 inhibitors, of which the majority was common for both tamoxifen- and fulvestrant-resistant cell lines. Two compounds, WP1130 and JNJ-7706621, exhibiting prominent preferential growth inhibition of antiestrogen-resistant cell lines, were selected for further studies. WP1130, a deubiquitinase inhibitor, induced caspase-mediated cell death in both tamoxifen- and fulvestrant-resistant cell lines by destabilization of the anti-apoptotic protein Mcl-1. Mcl-1 expression was found upregulated in the antiestrogen-resistant cell lines and depletion of Mcl-1 in resistant cells caused decreased viability. JNJ-7706621, a dual Aurora kinase and cyclin-dependent kinase inhibitor, specifically inhibited growth and caused G2 phase cell cycle arrest of the tamoxifen-resistant cell lines. Knockdown studies showed that Aurora kinase A is essential for growth of the tamoxifen-resistant cells and inhibition of Aurora kinase A resensitized tamoxifen-resistant cells to tamoxifen treatment. Preferential growth inhibition by WP1130 and JNJ-7706621 was also found in T47D-derived tamoxifen-resistant cell lines, pointing at Mcl-1 and Aurora kinase A as potential treatment targets. In addition, tumor samples from 244 estrogen receptor-positive breast cancer patients treated with adjuvant tamoxifen showed that higher expression level of Aurora kinase A was significantly associated with shorter disease-free and overall survival, demonstrating the potential of Aurora kinase A as a biomarker for tamoxifen resistance.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/onc.2014.351Titel-ID: cdi_proquest_miscellaneous_1722168002
- Format
- –
- Schlagworte
- 13/31, 13/51, 13/95, 631/67/1347, 631/67/1857, 631/80/83, 96/47, Antiestrogens, Apoptosis, Apoptosis - drug effects, Apoptosis - genetics, Aurora kinase, Aurora Kinase A - antagonists & inhibitors, Aurora Kinase A - genetics, Aurora Kinase A - metabolism, Biomarkers, Biomarkers, Tumor - genetics, Biomarkers, Tumor - metabolism, Breast cancer, Breast Neoplasms - drug therapy, Breast Neoplasms - genetics, Breast Neoplasms - metabolism, Caspase, Caspases - metabolism, Cell Biology, Cell cycle, Cell death, Cell Line, Tumor, Cell Proliferation - drug effects, Cell Proliferation - genetics, Cyanoacrylates - pharmacology, Cyclin-dependent kinase, Cyclin-dependent kinases, Drug Resistance, Neoplasm - drug effects, Drug Resistance, Neoplasm - genetics, Drug Screening Assays, Antitumor, Enzyme inhibitors, Estradiol - analogs & derivatives, Estradiol - pharmacology, Estrogen Antagonists - pharmacology, Estrogens, Fulvestrant, G2 phase, G2 Phase Cell Cycle Checkpoints - drug effects, G2 Phase Cell Cycle Checkpoints - genetics, Health aspects, Human Genetics, Humans, Internal Medicine, Kinases, MCF-7 Cells, Mcl-1 protein, Medicine, Medicine & Public Health, Molecular modelling, Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors, Myeloid Cell Leukemia Sequence 1 Protein - genetics, Myeloid Cell Leukemia Sequence 1 Protein - metabolism, Oncology, original-article, Protein expression, Protein Kinase Inhibitors - pharmacology, Pyridines - pharmacology, Receptors, Estrogen - metabolism, RNA Interference, Signal transduction, Survival Analysis, Tamoxifen, Tamoxifen - pharmacology, Therapeutic applications, Triazoles - pharmacology