Please use this identifier to cite or link to this item: http://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; Receptor, Epidermal Growth Factor; 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; Checkpoint Kinase 1
Rights: © 2014 American Association for Cancer Research
RMID: 0030023914
DOI: 10.1158/1078-0432.CCR-14-0048
Grant ID: http://purl.org/au-research/grants/arc/FT130101417
Appears in Collections:Medicine publications

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