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

Beibei Zhai,Jeffrey Bacha,Anne Steinø,Dennis Brown,Mads Daugaard

doi:10.1038/s41419-018-1069-9

Abstract

1,2:5,6-Dianhydrogalactitol (DAG) is a bifunctional DNA-targeting agent causing N7-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 N7-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 N7-guanine crosslink-induced cytotoxicity in cancer cells and provides a rationale for using DAG analogs to treat HR-deficient tumors.

Highlights

Historical data from preclinical studies and clinical trials support anti-neoplastic effects of 1,2:5,6-dianhydrogalactitol (DAG) analogs in a variety of cancer types, including leukemia, brain, cervical, ovarian, and lung cancers[1,2,3,4,5,6]
Loss of lung cancer cell viability after DAG treatment To investigate the effects of DAG on lung cancer cells, we evaluated the cytotoxic activities of VAL-083 in a panel of nonsmall cell lung cancer (NSCLC) cell lines
DAG induces persistent DNA damage in lung cancer cells Many chemotherapeutic drugs work by inducing different types of DNA damage in rapid-dividing cancer cells

Summary

Introduction

Historical data from preclinical studies and clinical trials support anti-neoplastic effects of 1,2:5,6-dianhydrogalactitol (DAG) analogs in a variety of cancer types, including leukemia, brain, cervical, ovarian, and lung cancers[1,2,3,4,5,6]. In China, DAG is approved for the treatment of lung cancer[7]. Lung cancer is the leading cause of cancer-related deaths. The 5-year relative survival rate for lung cancer is 15% for men and 21% for women. There are two major types of lung cancer, nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for 80–85% of all lung cancer patients present with stage IV metastatic disease. The median overall survival for patients with stage IV NSCLC is 4 months, and the 5-year survival rate is only 4%8–10

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Conclusion