Abstract
BackgroundThe 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).MethodsWe 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.ResultsThe 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.ConclusionsWhile 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.
Highlights
Radiation therapy (RT) plays an important role in the treatment of locally advanced pancreatic cancers, but its effect is limited by the sensitivity of adjacent normal tissues, and the innate radioresistance of these cancers (PMID:24462333)
The BRCA2 mutated and wild type tumours showed similar radiation sensitivity, and treatment with olaparib did not further sensitize either model when compared to ionizing radiation (IR) alone
While poly (ADP-ribose) polymerase (PARP) inhibition has been shown to be effective in BRCA-mutated breast and ovarian cancers, it is less well established in pancreatic cancer patients
Summary
Radiation therapy (RT) plays an important role in the treatment of locally advanced pancreatic cancers, but its effect is limited by the sensitivity of adjacent normal tissues, and the innate radioresistance of these cancers (PMID:24462333). Homologous recombination faithfully restores the DNA sequence by using the sister chromatid as a template, and its activity is restricted to the late S and G2 phases of the cell cycle where the sister chromatid is present. It repairs multiple types of DNA damage, including single stranded DNA (ssDNA), DSBs and DNA cross-links [1, 2]. The BRCA2 gene product plays an important role in DNA double strand break repair. 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)
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