吉西他滨和 CHK1 抑制增强了针对胰腺导管腺癌的 EGFR 导向放射免疫治疗。

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

机构信息

Authors' Affiliations: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland; The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research; St Vincent's Clinical School, Faculty of Medicine, University of NSW; Department of Anatomical Pathology, SYDPATH, St Vincent's Hospital, Darlinghurst, New South Wales; Australian Pancreatic Cancer Genome Initiative, for the full list of contributors see http://www.pancreaticcancer.net.au/apgi/collaborators; Cancer Clinical Trials Unit, Royal Adelaide Hospital Cancer Centre, and Centre for Cancer Biology, SA Pathology; School of Medicine, University of Adelaide, Adelaide, Australia; and Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United KingdomAuthors' Affiliations: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland; The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research; St Vincent's Clinical School, Faculty of Medicine, University of NSW; Department of Anatomical Pathology, SYDPATH, St Vincent's Hospital, Darlinghurst, New South Wales; Australian Pancreatic Cancer Genome Initiative, for the full list of contributors see http://www.pancreaticcancer.net.au/apgi/collaborators; Cancer Clinical Trials Unit, Royal Adelaide Hospital Cancer Centre, and Centre for Cancer Biology, SA Pathology; School of Medicine, University of Adelaide, Adelaide, Australia; and Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.

出版信息

Clin Cancer Res. 2014 Jun 15;20(12):3187-97. doi: 10.1158/1078-0432.CCR-14-0048. Epub 2014 May 16.

DOI:10.1158/1078-0432.CCR-14-0048

PMID:24838526

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.

摘要

目的

开发一种联合化疗、CHK1 抑制和 EGFR 靶向放射免疫治疗的有效联合疗法，用于治疗胰腺导管腺癌（PDAC）。

实验设计

确定吉西他滨、CHK1 抑制剂 PF-477736 和镥-177（177Lu）标记的抗 EGFR 抗体联合应用的最大耐受剂量。使用来自成熟细胞系、最近建立的患者来源细胞系和新鲜患者来源异种移植瘤的 PDAC 模型研究了这种三联组合疗法。研究了肿瘤对 177Lu-抗 EGFR 抗体的积累、肿瘤起始细胞的存活、DNA 损伤的诱导、细胞死亡和肿瘤组织退化。

结果

吉西他滨和 CHK1 抑制剂 PF-477736 与 177Lu-抗 EGFR 抗体联合应用在小鼠中是可以耐受的。该三联疗法对已建立的肿瘤有效，并可预防四种细胞系衍生和一种患者来源异种移植瘤模型中 PDAC 的复发。这种精确的反应与肿瘤起始细胞的丢失有关，可通过流式细胞术分析和用来自治疗小鼠的肿瘤进行治疗-naive 小鼠的二次植入来测量。在患者来源的异种移植瘤中检测到广泛的 DNA 损伤、凋亡和肿瘤退化。从机制上讲，我们观察到 CHK1 抑制导致 CDC25A 稳定，从而抑制了吉西他滨诱导的 S 期阻滞，以及 EGFR 抑制导致经典（ERK1/2 磷酸化）和非经典 EGFR 信号（RAD51 降解）减少。