Targeted Radiosensitization of Cells Expressing Truncated DNA Polymerase β

Ionizing radiation (IR) is an effective anticancer treatment, although failures still occur. To improve radiotherapy, tumor-targeted strategies are needed to increase radiosensitivity of tumor cells, without influencing normal tissue radiosensitivity. Base excision repair (BER) and single-strand break repair (SSBR) contribute to the determination of sensitivity to IR. A crucial protein in BER/SSBR is DNA polymerase beta (pol beta). Aberrant pol beta expression is commonly found in human tumors and leads to inhibition of BER. Here, we show that truncated pol beta variant (pol beta-Delta)-expressing cells depend on homologous recombination (HR) for survival after IR, indicating that a considerable fraction of pol beta-Delta-induced lesions are subject to repair by HR. Increased sensitization was found not to result from involvement in DNA-dependent protein kinase-dependent nonhomologous end joining, the other major double-strand break repair pathway. Caffeine and the ATM inhibitor Ku55933 cause pol beta-Delta-dependent radiosensitization. Consistent with the observed HR dependence and the known HR-modulating activity of ATM, pol beta-Delta-expressing cells showed increased radiosensitization after BRCA2 knockdown that is absent under ATM-inhibited conditions. Our data suggest that treatment with HR modulators is a promising therapeutic strategy for exploiting defects in the BER/SSBR pathway in human tumors. Cancer Res; 70(21); 8706-14. (C)2010 AACR.