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https://hdl.handle.net/2440/92255
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Type: | Journal article |
Title: | Gemcitabine and CHK1 inhibition potentiate EGFR-directed radioimmunotherapy against pancreatic ductal adenocarcinoma |
Author: | Al-Ejeh, F. Pajic, M. Shi, W. Kalimutho, M. Miranda, M. Nagrial, A. Chou, A. Biankin, A. Grimmond, S. Brown, M. Khanna, K. |
Citation: | Clinical Cancer Research, 2014; 20(12):3187-3197 |
Publisher: | American Association for Cancer Research |
Issue Date: | 2014 |
ISSN: | 1078-0432 1557-3265 |
Statement of Responsibility: | Fares Al-Ejeh, Marina Pajic, Wei Shi, Murugan Kalimutho, Mariska Miranda, Adnan M. Nagrial, Angela Chou, Andrew V. Biankin, Sean M. Grimmond, Michael P. Brown, and Kum Kum Khanna |
Abstract: | PURPOSE: To develop effective combination therapy against pancreatic ductal adenocarcinoma (PDAC) with a combination of chemotherapy, CHK1 inhibition, and EGFR-targeted radioimmunotherapy. EXPERIMENTAL DESIGN: Maximum tolerated doses were determined for the combination of gemcitabine, the CHK1 inhibitor PF-477736, and Lutetium-177 ((177)Lu)-labeled anti-EGFR antibody. This triple combination therapy was investigated using PDAC models from well-established cell lines, recently established patient-derived cell lines, and fresh patient-derived xenografts. Tumors were investigated for the accumulation of (177)Lu-anti-EGFR antibody, survival of tumor-initiating cells, induction of DNA damage, cell death, and tumor tissue degeneration. RESULTS: The combination of gemcitabine and CHK1 inhibitor PF-477736 with (177)Lu-anti-EGFR antibody was tolerated in mice. This triplet was effective in established tumors and prevented the recurrence of PDAC in four cell line-derived and one patient-derived xenograft model. This exquisite response was associated with the loss of tumor-initiating cells as measured by flow cytometric analysis and secondary implantation of tumors from treated mice into treatment-naïve mice. Extensive DNA damage, apoptosis, and tumor degeneration were detected in the patient-derived xenograft. Mechanistically, we observed CDC25A stabilization as a result of CHK1 inhibition with consequent inhibition of gemcitabine-induced S-phase arrest as well as a decrease in canonical (ERK1/2 phosphorylation) and noncanonical EGFR signaling (RAD51 degradation) as a result of EGFR inhibition. CONCLUSIONS: Our study developed an effective combination therapy against PDAC that has potential in the treatment of PDAC. |
Keywords: | Australian Pancreatic Cancer Genome Initiative Tumor Cells, Cultured Animals Mice, Inbred BALB C Mice, Inbred NOD Humans Mice Mice, SCID Carcinoma, Pancreatic Ductal Pancreatic Neoplasms DNA Damage Pyrazoles Benzodiazepinones Protein Kinases Deoxycytidine Antimetabolites, Antineoplastic Antibodies, Monoclonal Blotting, Western Immunoenzyme Techniques Radioimmunotherapy Combined Modality Therapy Xenograft Model Antitumor Assays Signal Transduction Apoptosis Cell Proliferation Phosphorylation Drug Synergism Female ErbB Receptors Checkpoint Kinase 1 Gemcitabine |
Rights: | © 2014 American Association for Cancer Research |
DOI: | 10.1158/1078-0432.CCR-14-0048 |
Grant ID: | http://purl.org/au-research/grants/arc/FT130101417 |
Published version: | http://dx.doi.org/10.1158/1078-0432.ccr-14-0048 |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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