Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities
| العنوان: | Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities |
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| المؤلفون: | Pancholi, Sunil, Ribas, Ricardo, Simigdala, Nikiana, Schuster, Eugene, Nikitorowicz-Buniak, Joanna, Ressa, Anna, Gao, Qiong, Leal, Mariana Ferreira, Bhamra, Amandeep, Thornhill, Allan, Morisset, Ludivine, Montaudon, Elodie, Sourd, Laura, Fitzpatrick, Martin, Altelaar, Maarten, Johnston, Stephen R, Marangoni, Elisabetta, Dowsett, Mitch, Martin, Lesley-Ann, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics |
| المساهمون: | Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics |
| المصدر: | Oncogene, 39(25), 4781. Nature Publishing Group Oncogene |
| بيانات النشر: | Springer Science and Business Media LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, MAPK/ERK pathway, Cancer Research, Fulvestrant/administration & dosage, Pyridines, Nude, Drug Resistance, Cyclin-Dependent Kinase 4/genetics, Drug Resistance, Neoplasm/drug effects, Retinoblastoma Protein, Piperazines, Tamoxifen/administration & dosage, Mice, Breast cancer, 0302 clinical medicine, Neoplasm/drug effects, Antineoplastic Combined Chemotherapy Protocols, Receptors, Kinome, Piperazines/pharmacology, Fulvestrant, Inbred BALB C, Pyridines/pharmacology, Mice, Inbred BALB C, Tumor, Cyclin-Dependent Kinase 6/genetics, biology, Receptors, Estrogen/genetics, Cell cycle, Wee1, Receptors, Estrogen, 030220 oncology & carcinogenesis, MCF-7 Cells, Female, RNA Interference, medicine.drug, Mice, Nude, Breast Neoplasms, Breast Neoplasms/genetics, Palbociclib, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Article, Cell Line, 03 medical and health sciences, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Cancer models, Protein Kinase Inhibitors, Molecular Biology, Retinoblastoma Protein/genetics, Cyclin-Dependent Kinase 4, Estrogen/genetics, Cyclin-Dependent Kinase 6, Xenograft Model Antitumor Assays, Tamoxifen, 030104 developmental biology, Xenograft Model Antitumor Assays/methods, Drug Resistance, Neoplasm, Protein Kinase Inhibitors/pharmacology, biology.protein, Cancer research, TSC2 |
| الوصف: | Combination of CDK4/6 inhibitors and endocrine therapy improves clinical outcome in advanced oestrogen receptor (ER)-positive breast cancer, however relapse is inevitable. Here, we show in model systems that other than loss ofRB1few gene-copy number (CN) alterations are associated with irreversible-resistance to endocrine therapy and subsequent secondary resistance to palbociclib. Resistance to palbociclib occurred as a result of tumour cell re-wiring leading to increased expression ofEGFR, MAPK, CDK4, CDK2, CDK7, CCNE1andCCNE2. Resistance altered the ER genome wide-binding pattern, leading to decreased expression of ‘classical’ oestrogen-regulated genes and was accompanied by reduced sensitivity to fulvestrant and tamoxifen. Persistent CDK4 blockade decreased phosphorylation of tuberous sclerosis complex 2 (TSC2) enhancing EGFR signalling, leading to the re-wiring of ER. Kinome-knockdown confirmed dependency on ERBB-signalling and G2/M–checkpoint proteins such as WEE1, together with the cell cycle master regulator, CDK7. Noteworthy, sensitivity to CDK7 inhibition was associated with loss of ER andRB1CN. Overall, we show that resistance to CDK4/6 inhibitors is dependent on kinase re-wiring and the redeployment of signalling cascades previously associated with endocrine resistance and highlights new therapeutic networks that can be exploited upon relapse after CDK4/6 inhibition. |
| وصف الملف: | application/pdf |
| تدمد: | 1476-5594 0950-9232 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::83726164166fa3f899deca8969edd34c https://doi.org/10.1038/s41388-020-1284-6 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....83726164166fa3f899deca8969edd34c |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14765594 09509232 |
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