Journal
CLINICAL CANCER RESEARCH
Volume 20, Issue 12, Pages 3187-3197Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-0048
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Funding
- Cancer Council New South Wales Innovator Grant [IG09-04]
- Justin McDonald Pancreatic Cancer grant
- Australian Research Council (ARC) Future Fellowship [FT130101417]
- National Health and Medical Research Council (NHMRC) Program Grant
- Australian Research Council [FT130101417] Funding Source: Australian Research Council
- Cancer Research UK [17263] Funding Source: researchfish
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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 (Lu-177)-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 Lu-177-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 Lu-177-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-naive 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. (C) 2014 AACR.
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