The poly(ADP-ribose) polymerase inhibitor ABT-888 reduces radiation-induced nuclear EGFR and augments head and neck tumor response to radiotherapy

Somaira Nowsheen, James A. Bonner, Eddy S. Yang

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Background and purpose: Current therapies for head and neck cancer frequently are not curative, necessitating novel therapeutic strategies. Thus, we studied whether inhibition of poly(ADP-Ribose) polymerase (PARP), a key DNA repair enzyme, could improve efficacy of radiotherapy in human head and neck cancer. Materials and methods: UM-SCC1, UM-SCC5, UM-SCC6, and FaDu human head and neck cancer cellular susceptibility to the PARP inhibitor (PARPi) ABT-888 and/or radiation (IR) was assessed using colony formation assays. DNA damage was evaluated using the alkaline comet assay and immunostaining for γ-H2AX foci. Non-homologous end-joining (NHEJ) mediated repair was measured using phospho-DNA-Pk foci. Epidermal growth factor receptor (EGFR) location was assessed by immunostaining. Poly ADP-Ribose polymerization (PAR) levels were assessed using immunoblotting. Results: Human head and neck cancer cells exhibited enhanced cytotoxicity with IR and ABT-888 compared to either agent alone. This increased susceptibility correlated with reduced nuclear EGFR, attenuation of NHEJ, and persistence of DNA damage following IR. Interestingly, a subset of head and neck cancer cells which had elevated basal PAR levels was susceptible to PARPi alone. Conclusions: Combining radiotherapy and PARP inhibition may improve outcomes and quality of life for head and neck cancer patients treated with radiotherapy. Furthermore, this novel strategy may also be feasible in other tumor types. Moreover, PAR levels should be investigated as a potential biomarker for tumor susceptibility to PARP inhibition.

Original languageEnglish
Pages (from-to)331-338
Number of pages8
JournalRadiotherapy and Oncology
Volume99
Issue number3
DOIs
StatePublished - Jun 2011

Bibliographical note

Funding Information:
This work was supported by the Center for Clinical and Translational Science (CCTS) Translational Research Intramural Pilot Grant Program (grant number 5UL1 RR025777-04 ) from the NIH National Center for Research Resources, the State of Alabama Investment Pool for Action (IMPACT) funds from the University of Alabama-Birmingham School of Medicine, and developmental support from the Comprehensive Cancer Center and Department of Radiation Oncology at the University of Alabama-Birmingham (to E.S.Y.).

Keywords

  • ABT-888
  • Biomarker
  • DNA damage
  • DNA repair
  • EGFR
  • H2AX
  • Head and neck cancer
  • Non-homologous end-joining (NHEJ)
  • Nuclear import
  • PARP
  • Radiation

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Radiology Nuclear Medicine and imaging

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