The mechanisms involved in the resistance of estrogen receptor-positive breast cancer cells to palbociclib are multiple and change over time
| العنوان: | The mechanisms involved in the resistance of estrogen receptor-positive breast cancer cells to palbociclib are multiple and change over time |
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| المؤلفون: | Mayu Ono, Takaaki Oba, Ken-ichi Ito, Tomohiro Shibata |
| المصدر: | Journal of Cancer Research and Clinical Oncology |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cyclin-dependent kinase inhibitor, Cancer Research, Pyridines, Receptor, ErbB-2, Estrogen receptor, Antineoplastic Agents, Breast Neoplasms, Cell Cycle Proteins, Palbociclib, Piperazines, 03 medical and health sciences, chemistry.chemical_compound, Breast cancer, 0302 clinical medicine, Cell Line, Tumor, Humans, Dinaciclib, Retinoblastoma gene, Protein Kinase Inhibitors, biology, Kinase, Cell Cycle, Estrogen Receptor alpha, Retinoblastoma protein, General Medicine, Cell cycle, 030104 developmental biology, Receptors, Estrogen, Oncology, chemistry, Drug Resistance, Neoplasm, Drug resistance, 030220 oncology & carcinogenesis, MCF-7 Cells, biology.protein, Cancer research, Cyclin-dependent kinase 6, Signal transduction, Original Article – Cancer Research, Signal Transduction |
| الوصف: | Purpose Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used for the treatment of advanced estrogen receptor (ER)-positive breast cancer. To develop a treatment strategy for cancers resistant to CDK4/6 inhibitors, here, we established palbociclib-resistant sublines and analyzed their resistance mechanisms. Methods Palbociclib-resistant sublines were established from T47D and MCF7 cells. Sensitivity to other drugs was assessed via the WST assay. Altered expression/phosphorylation of proteins related to signal transduction and cell cycle regulation was examined using western blotting. Copy number alterations and mutations in the retinoblastoma (RB1) gene were also analyzed. Results Although an increase in CDK6 and decrease in retinoblastoma protein (Rb) expression/phosphorylation were commonly observed in the resistant sublines, changes in other cell cycle-related proteins were heterogeneous. Upon extended exposure to palbociclib, the expression/phosphorylation of these proteins became altered, and the long-term removal of palbociclib did not restore the Rb expression/phosphorylation patterns. Consistently a copy number decrease, as well as RB1 mutations were detected. Moreover, although the resistant sublines exhibited cross-resistance to abemaciclib, their response to dinaciclib was the same as that of wild-type cells. Of note, the cell line exhibiting increased mTOR phosphorylation also showed a higher sensitivity to everolimus. However, the sensitivity to chemotherapeutic agents was unchanged in palbociclib-resistant sublines. Conclusion ER-positive breast cancer cells use multiple molecular mechanisms to survive in the presence of palbociclib, suggesting that targeting activated proteins may be an effective strategy to overcome resistance. Additionally, palbociclib monotherapy induces mutations and copy number alterations in the RB1 gene. |
| تدمد: | 1432-1335 0171-5216 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bab93e74838ffc7d5b4d1870bc35e0d6 https://doi.org/10.1007/s00432-021-03722-3 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....bab93e74838ffc7d5b4d1870bc35e0d6 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14321335 01715216 |
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