DNA Double-strand Break Signaling Is a Therapeutic Target in Head and Neck Cancer

Abstract

Background: Head and neck cancer (HNC) is common worldwide. Given poor outcomes for patients with HNC, research into targeted therapies is needed. Ataxia telangiectasia mutated (ATM) is a DNA damage kinase which is activated by double-strand DNA breaks. We tested the effects of a novel ATM inhibitor on HNC cell lines and xenografts.

Materials and methods: p53-Binding protein 1 and phosphorylated ATM were localized in cultured cells by immunofluorescence microscopy. Protein expression was determined by western blot. Tumor xenografts were established by injecting HNC lines into immunocompromised mice. Tumor sections were characterized by immunohistochemistry. Apoptotic cells were determined by terminal transferase-mediated dUTP nick-end labeling assay.

Results: ATM inhibition increased double-strand DNA breaks at replication foci in HNC cell lines. ATM inhibition affected cell-cycle regulatory protein expression, blocked cell-cycle progression at the G₂/M phase and resulted in apoptosis.

Conclusion: ATM inhibition may be therapeutically useful in treating HNC.

Keywords: Ataxia telangiectasia mutated; biomarker; human papillomavirus; targeted therapy.