Dianhydrogalactitol induces replication-dependent DNA damage in tumor cells preferentially resolved by homologous recombination

• Published in: Cell death & disease Vol. 9; no. 10; pp. 1016 - 10
• Main Authors: Zhai, Beibei, Steinø, Anne, Bacha, Jeffrey, Brown, Dennis, Daugaard, Mads
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.10.2018; Springer Nature B.V
• Subjects: 13; 13/89; 14; 14/19; 38; 38/109; 82; 82/1; 96; 96/31; Alkylation; Antibodies; Antitumor activity; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell cycle; Clinical trials; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; Glioblastoma; Guanine; Homologous recombination; Immunology; Life Sciences; Lung cancer; Molecular modelling; Non-small cell lung carcinoma; Replication; S phase; Tumor cells; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-1069-9

1,2:5,6-Dianhydrogalactitol (DAG) is a bifunctional DNA-targeting agent causing N 7 -guanine alkylation and inter-strand DNA crosslinks currently in clinical trial for treatment of glioblastoma. While preclinical studies and clinical trials have demonstrated antitumor activity of DAG in a variety of malignancies, understanding the molecular mechanisms underlying DAG-induced cytotoxicity is essential for proper clinical qualification. Using non-small cell lung cancer (NSCLC) as a model system, we show that DAG-induced cytotoxicity materializes when cells enter S phase with unrepaired N 7 -guanine DNA crosslinks. In S phase, DAG-mediated DNA crosslink lesions translated into replication-dependent DNA double-strand breaks (DSBs) that subsequently triggered irreversible cell cycle arrest and loss of viability. DAG-treated NSCLC cells attempt to repair the DSBs by homologous recombination (HR) and inhibition of the HR repair pathway sensitized NSCLC cells to DAG-induced DNA damage. Accordingly, our work describes a molecular mechanism behind N 7 -guanine crosslink-induced cytotoxicity in cancer cells and provides a rationale for using DAG analogs to treat HR-deficient tumors.