Academic Journal
Inhibition of the Growth of Patient-Derived Pancreatic Cancer Xenografts with the MEK Inhibitor Trametinib Is Augmented by Combined Treatment with the Epidermal Growth Factor Receptor/HER2 Inhibitor Lapatinib
| العنوان: | Inhibition of the Growth of Patient-Derived Pancreatic Cancer Xenografts with the MEK Inhibitor Trametinib Is Augmented by Combined Treatment with the Epidermal Growth Factor Receptor/HER2 Inhibitor Lapatinib |
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| المؤلفون: | Dustin M. Walters, James M. Lindberg, Sara J. Adair, Timothy E. Newhook, Catharine R. Cowan, Jayme B. Stokes, Cheryl A. Borgman, Edward B. Stelow, Bryce T. Lowrey, Maria E. Chopivsky, Tona M. Gilmer, John T. Parsons, Todd W. Bauer |
| المصدر: | Neoplasia: An International Journal for Oncology Research, Vol 15, Iss 2, Pp 143-155 (2013) |
| بيانات النشر: | Elsevier, 2013. |
| سنة النشر: | 2013 |
| المجموعة: | LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| مصطلحات موضوعية: | Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: | Mutations of the oncogene KRAS are important drivers of pancreatic cancer progression. Activation of epidermal growth factor receptor (EGFR) and human EGFR2 (HER2) is observed frequent in pancreatic adenocarcinomas. Because of co-activation of these two signaling pathways, we assessed the efficacy of inhibition of EGFR/HER2 receptors and the downstream KRAS effector, mitogen-activated protein kinase/extracellular-signal regulated kinase (ERK) kinase 1 and 2 (MEK1/2), on pancreatic cancer proliferation in vitro and in a murine orthotopic xenograft model. Treatment of established and patient-derived pancreatic cancer cell lines with the MEK1/2 inhibitor trametinib (GSK1120212) inhibited proliferation, and addition of the EGFR/HER2 inhibitor lapatinib enhanced the inhibition elicited by trametinib in three of eight cell lines. Importantly, in the orthotopic xenograft model, treatment with lapatinib and trametinib resulted in significantly enhanced inhibition of tumor growth relative to trametinib treatment alone in four of five patient-derived tumors tested and was, in all cases, significantly more effective in reducing the size of established tumors than treatment with lapatinib or trametinib alone. Acute treatment of established tumors with trametinib resulted in an increase in AKT2 phosphorylation that was blunted in mice treated with both trametinib and lapatinib. These data indicate that inhibition of the EGFR family receptor signaling may contribute to the effectiveness of MEK1/2 inhibition of tumor growth possibly through the inhibition of feedback activation of receptor tyrosine kinases in response to inhibition of the RAS-RAF-MEK-ERK pathway. These studies provide a rationale for assessing the co-inhibition of these pathways in the treatment of pancreatic cancer patients. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1476-5586 1522-8002 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S1476558613800255; https://doaj.org/toc/1476-5586; https://doaj.org/toc/1522-8002 |
| DOI: | 10.1593/neo.121712 |
| URL الوصول: | https://doaj.org/article/9fb804b7b7d4409cb4093fdefaf8b552 |
| رقم الانضمام: | edsdoj.9fb804b7b7d4409cb4093fdefaf8b552 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14765586 15228002 |
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| DOI: | 10.1593/neo.121712 |