Academic Journal
MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma
| العنوان: | MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma |
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| المؤلفون: | Castillo, Lesley E., Young, Adelaide I., Mawson, Amanda, Schafranek, Pia, Steinmann, Angela, Nessem, Danielle, Parkin, Ashleigh, Johns, Amber L., Chou, Angela, Law, Andrew M., Lucas, Morghan C., Murphy, Kendelle J., Deng, Niantao, Gallego-Ortega, David, Caldon, Catherine E., Australian Pancreatic Cancer Genome Initiative, Merrett, Neil D. (R14270), Timpson, Paul, Pajic, Marina, Ormandy, Christopher J., Oakes, Samantha R. |
| بيانات النشر: | U.K., Nature Publishing Group |
| سنة النشر: | 2020 |
| المجموعة: | University of Western Sydney (UWS): Research Direct |
| مصطلحات موضوعية: | 321199 - Oncology and carcinogenesis not elsewhere classified, 209999 - Other health not elsewhere classified, pancreatic duct, adenocarcinoma, genomes, antineoplastic agent, protein-tyrosine kinase |
| الوصف: | Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. It is phenotypically heterogeneous with a highly unstable genome and provides few common therapeutic targets. We found that MCL1, Cofilin1 (CFL1) and SRC mRNA were highly expressed by a wide range of these cancers, suggesting that a strategy of dual MCL-1 and SRC inhibition might be efficacious for many patients. Immunohistochemistry revealed that MCL-1 protein was present at high levels in 94.7% of patients in a cohort of PDACs from Australian Pancreatic Genome Initiative (APGI). High MCL1 and Cofilin1 mRNA expression was also strongly predictive of poor outcome in the TCGA dataset and in the APGI cohort. In culture, MCL-1 antagonism reduced the level of the cytoskeletal remodeling protein Cofilin1 and phosphorylated SRC on the active Y416 residue, suggestive of reduced invasive capacity. The MCL-1 antagonist S63845 synergized with the SRC kinase inhibitor dasatinib to reduce cell viability and invasiveness through 3D-organotypic matrices. In preclinical murine models, this combination reduced primary tumor growth and liver metastasis of pancreatic cancer xenografts. These data suggest that MCL-1 antagonism, while reducing cell viability, may have an additional benefit in increasing the antimetastatic efficacy of dasatinib for the treatment of PDAC. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | |
| اللغة: | English |
| Relation: | Oncogene--0950-9232--1476-5594 Vol. 39 Issue. 8 pp: 1821-1829 |
| DOI: | 10.1038/s41388-019-1091-0 |
| الاتاحة: | https://doi.org/10.1038/s41388-019-1091-0 http://hdl.handle.net/1959.7/uws:57858 |
| Rights: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. |
| رقم الانضمام: | edsbas.42F0C06D |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41388-019-1091-0 |
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