Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts

• Published in: PloS one 2016-12, Vol.11 (12), p.e0167272-e0167272
• Main Authors: Lohse, Ines, Kumareswaran, Ramya, Cao, Pinjiang, Pitcher, Bethany, Gallinger, Steven, Bristow, Robert G, Hedley, David W
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Animals; Antineoplastic Agents - therapeutic use; Apoptosis; Biology and life sciences; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Cancer; Cancer therapies; Care and treatment; Cell cycle; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Combined Modality Therapy - methods; Combined treatment; Comparative analysis; Damage assessment; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Health aspects; Health care networks; Humans; Hypoxia; Inhibition; Ionizing radiation; Medical research; Medicine and Health Sciences; Mice; Mice, SCID; Mutation; Olaparib; Ovarian cancer; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - radiotherapy; Phthalazines - therapeutic use; Physical Sciences; Piperazines - therapeutic use; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Prostate cancer; Radiation; Radiation, Ionizing; Radiation-Sensitizing Agents - therapeutic use; Radiosensitization; Ribose; Rodents; Sensitivity; Targeted cancer therapy; Tumors; Xenograft Model Antitumor Assays - methods; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0167272

The BRCA2 gene product plays an important role in DNA double strand break repair. Therefore, we asked whether radiation sensitivity of pancreatic cancers developing in individuals with germline BRCA2 mutations can be enhanced by agents that inhibit poly (ADP-ribose) polymerase (PARP). We compared the sensitivity of two patient-derived pancreatic cancer xenografts, expressing a truncated or wild type BRCA 2, to ionizing radiation alone or in combination with olaparib (AZD-2281). Animals were treated with either a single dose of 12Gy, 7 days of olaparib or 7 days of olaparib followed by a single dose of 12Gy. Response was assessed by tumour growth delay and the activation of damage response pathways. The BRCA2 mutated and wild type tumours showed similar radiation sensitivity, and treatment with olaparib did not further sensitize either model when compared to IR alone. While PARP inhibition has been shown to be effective in BRCA-mutated breast and ovarian cancers, it is less well established in pancreatic cancer patients. Our results show no radiosensitization in a germline BRCA 2 mutant and suggest that combining PARP inhibition and IR may not be beneficial in BRCA 2 related pancreatic tumors.