Abstract A109: DNA-damaging agent dianhydrogalactitol (VAL-083) targets HR repair pathway and suggests combination therapy with topoisomerase and PARP inhibitors

Abstract

Abstract DNA damage repair (DDR) describes the network of pathways that are responsible for minimizing the effect of daily DNA damage such as mismatched base pairs, single-strand breaks, and double-strand breaks (DSBs). Multiple DNA repair pathways are known, including mismatch repair (MMR), O6-methylguanine DNA methyltransferase (MGMT), non-homologous end joining (NHEJ), and homologous recombination (HR), which act either by repairing the damage, arresting cell growth or, if necessary, promoting cell death. DDR defects are a hallmark of cancer development, rendering the cancer cells highly sensitive to targeted DNA-damaging agents. Dianhydrogalactitol (VAL-083) is a first-in-class DNA-damaging agent that rapidly induces interstrand crosslinks at guanine-N7 causing persistent DNA DSBs that, if left unrepaired, are lethal to the cancer cells. We have previously shown that VAL-083 treatment leads to DNA damage that activates HR and is independent of MGMT DNA repair. Furthermore, we recently showed that VAL-083 induces persistent S/G2 phase cell cycle arrest, proposing potential for combination treatment with S-phase specific DNA-targeting agents such as topoisomerase and PARP inhibitors. In this study, biochemical and microscopic analyses of DNA repair markers were employed to investigate the VAL-083-induced DNA damage response in different MMR- or NHEJ-proficient/deficient cancer cell lines. VAL-083’s activity against HR-impaired cancer cells was also investigated using BRCA1 siRNAs. VAL-083 combination with topoisomerase inhibitors, etoposide (Top2) and camptothecin (Top1), and PARP inhibitor olaparib was investigated in PC3, A549, and A2780 cancer cells. Here, we report VAL-083 is a DNA-targeting agent that induces DNA DSBs, irreversible S/G2-phase cell cycle arrest, activation of the HR repair pathway, and ultimately cell death through mechanisms independent of MGMT, MMR, and NHEJ. We also show increased VAL-083 cytotoxicity against HR-impaired (BRCA1-knockdown) A2780 cancer cells, further supporting HR as the main repair pathway involved in VAL-083-induced cancer cell death, demonstrating the potential of VAL-083 for the treatment of HR-impaired tumors. Additionally, we report synergy between VAL-083 and topoisomerase inhibitors etoposide and camptothecin in A549 and PC3 cancer cell lines, as well as superadditivity with PARP inhibitor olaparib in A2780 cancer cells. Taken together, our results demonstrate a distinct DNA-targeting mechanism of VAL-083, leading to the ability to overcome MGMT- , MMR- , and NHEJ-related chemoresistance to common DNA-targeting agents, including temozolomide and nitrosoureas. In addition, increased VAL-083 cytotoxic effect in cancer cells with impaired HR and synergy/superadditivity with topoisomerase and PARP inhibitors was identified. Citation Format: Beibei Zhai, Guangan He, Anne Steino, Jeffrey A. Bacha, Dennis M. Brown, Zahid Siddik, Mads Daugaard. DNA-damaging agent dianhydrogalactitol (VAL-083) targets HR repair pathway and suggests combination therapy with topoisomerase and PARP inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A109.