Olaparib, monotherapy or with ionizing radiation, exacerbates DNA damage in normal tissues:insights from a new p21 reporter mouse

Many drugs targeting the DNA damage response are being developed as anti-cancer therapies, either as single agents or in combination with ionising radiation or other cytotoxic agents. Numerous clinical trials in this area are either in progress or planned. However, concerns remain about the potential of such treatments to increase toxicity to normal tissues. In order to address this issue, we have created a novel reporter mouse line through the simultaneous incorporation of multiple reporters, β-galactosidase and firefly luciferase, into the DNA damage-inducible p21 locus. We show that in situ β-galactosidase staining facilitates high fidelity mapping of p21 expression across multiple organs and tissues at single-cell resolution, whereas the luciferase reporter permits non-invasive bioluminescent imaging of p21 expression. Using this model, we have studied the capacity of a number of DNA damaging agents, including ionizing radiation, cisplatin, and etoposide to induce p21 expression in normal tissues. We have also studied the PARP inhibitor olaparib alone or in combination with ionizing radiation as well as cisplatin. A single exposure to olaparib alone caused DNA damage to cells in the mucosal layer lining mouse large intestine. It also exacerbated DNA damage induced in this organ and the kidney by co-administered ionizing radiation. These studies suggest that olaparib might be a carcinogen in man and illustrate the power of our new model to evaluate the safety of new therapeutic regimens involving combination therapies