Abstract 2549: Tyrosyl-DNA phosphodiesterase 1 (TDP1) is critical for the repair of DNA breaks induced by sapacitabine, a nucleoside antimetabolite in clinical trials targeted to ATM- and BRCA-deficient tumors

Abstract

Abstract 2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) is a nucleoside analogue and the active metabolite of the anticancer drug, sapacitabine. The cytotoxic activity of CNDAC is achieved by incorporation of its nucleoside triphosphate metabolite into genomic DNA during replication, which subsequently undergoes beta-elimination that generates a single-strand break with 3′-end blocking DNA lesion. Subsequent DNA replication converts the nick into a double strand break. Earlier investigations demonstrated that cells lacking homologous recombination function are sensitized 20- to 100-fold to CNDAC. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) efficiently hydrolyzes 3′-blocking ends, we tested its role in the repair of CNDAC-induced DNA lesions and the potential cellular tolerance to CNDAC. Here we show that cells lacking TDP1 (TDP1-/- DT40 cells) exhibited marked hypersensitivity to CNDAC indicating the importance of TDP1 for the repair of CNDAC-induced DNA damage. Although the 3′-end blocking DNA lesions caused by another arabinosyl-nucleoside analog, cytosine arabinoside (cytarabine, AraC) and the topoisomerase I inhibitor camptothecin (CPT) are also repaired by TDP1, inactivation of homologous recombination, including BRCA1 and BRCA2, rendered cells hypersensitive to CNDAC and CPT but not to AraC. On the other hand, cells lacking PARP1/2 were hypersensitive to CPT only. Consistent with earlier findings, DT40 cells deficient in BRCA1, BRCA2, FANCD2, and ATM were sensitized to CNDAC. Thus, the present study has identified TDP1 as an additional mechanism that contributes to the repair of CNDAC-induced DNA lesions. It also demonstrates the differential involvement of DNA repair pathways that underlie the resistance to CNDAC, AraC and camptothecins, and provides a rationale for using sapacitabine to treat various types of cancers with preexisting defects in DNA repair pathways. Citation Format: Muthana Al Abo, Xiaojun Liu, William Plunkett, Yves Pommier. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is critical for the repair of DNA breaks induced by sapacitabine, a nucleoside antimetabolite in clinical trials targeted to ATM- and BRCA-deficient tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2549. doi:10.1158/1538-7445.AM2015-2549