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

Fares Al-Ejeh, Marina Pajic, Wei Shi, Murugan Kalimutho, Mariska Miranda, Adnan M. Nagrial, Angela Chou, Andrew V. Biankin, Sean M. Grimmond, Australian Pancreatic Cancer Genome Initiative, Michael P. Brown, Kum Kum Khanna

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3187-3197
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number12
DOIs
Publication statusPublished - 15 Jun 2014
Externally publishedYes

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