Gemcitabine and CHK1 inhibition potentiate EGFR-directed radioimmunotherapy against pancreatic ductal adenocarcinoma

Al-Ejeh, Fares, Pajic, Marina, Shi, Wei, Kalimutho, Murugan, Miranda, Mariska, Nagrial, Adnan M., Chou, Angela, Biankin, Andrew V., Grimmond, Sean M., Brown, Michael P. and Khanna, Kum Kum (2014) Gemcitabine and CHK1 inhibition potentiate EGFR-directed radioimmunotherapy against pancreatic ductal adenocarcinoma. Clinical Cancer Research, 20 12: 3187-3197. doi:10.1158/1078-0432.CCR-14-0048


Author Al-Ejeh, Fares
Pajic, Marina
Shi, Wei
Kalimutho, Murugan
Miranda, Mariska
Nagrial, Adnan M.
Chou, Angela
Biankin, Andrew V.
Grimmond, Sean M.
Brown, Michael P.
Khanna, Kum Kum
Title Gemcitabine and CHK1 inhibition potentiate EGFR-directed radioimmunotherapy against pancreatic ductal adenocarcinoma
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1557-3265
1078-0432
Publication date 2014-06-15
Year available 2014
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-14-0048
Open Access Status
Volume 20
Issue 12
Start page 3187
End page 3197
Total pages 11
Place of publication Philadelphia PA, United States
Publisher American Association for Cancer Research
Collection year 2015
Language eng
Formatted 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 (177Lu)–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 177Lu-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 177Lu-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. Clin Cancer Res; 20(12); 3187–97.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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