PARP Inhibitor Olaparib Enhances the Efficacy of Radiotherapy on Xrcc2-deficient Colorectal Cancer Cells

Abstract Background: Loss of XRCC2 compromises DNA damage repairs, and induced DNA damage burdens may increase the reliance on PARP-dependent DNA repairs of cancer cells to render cell susceptibility to PARP inhibitor therapy. Here, we study if XRCC2 loss sensitizes colorectal cancer(CRC) to PARP inhibitor in combination with radiotherapy (RT).Methods: The relationships between the expression of XRCC2 and PARP with patient outcome were investigated in 167 patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiotherapy (neoCRT). The in vitro radiosensitizing effects of olaparib were tested in XRCC2-deficient CRC using a clonogenic survival assay, determination of γH2AX foci, and measurement of β-galactosidase activity. An in vivo mouse xenograft model was used to determine the effect of olaparib on sensitization of tumors to ionizing radiation (IR).Results: High levels of XRCC2 or PARP1 were significantly associated with poor overall survival (OS) in patients with LARC who received neoCRT, co-expression analyses found low PARP1 and low XRCC2 expression have better OS. Our in vitro experiments indicated that olaparib+IR reduced clonogenic survival, increased persistent DNA damage, and prolonged cell cycle arrest and senescence in XRCC2-deficient cells relative to wild-type cells. Furthermore, our mouse xenograft experiments indicated that RT+olaparib had greater anti-tumor effects and led to long-term remission in mice with XRCC2-deficient tumors.Conclusions: XRCC2-deficient CRC acquire high sensitivity to PARP inhibition after IR treatment. Our preclinical findings provide a rationale for the use of Olaparib as a radiosensitizer for treatment of XRCC2-deficient CRC.