Article thumbnail

Cetuximab Augments Cytotoxicity with Poly (ADP-Ribose) Polymerase Inhibition in Head and Neck Cancer

By Somaira Nowsheen, James A. Bonner, Albert F. LoBuglio, Hoa Trummell, Alexander C. Whitley, Michael C. Dobelbower and Eddy S. Yang

Abstract

Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing tumors with defective DNA repair. In this study, we demonstrate that C225 enhances cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. The mechanism of increased susceptibility to C225 and PARPi involves C225-mediated reduction of non-homologous end-joining (NHEJ)- and homologous recombination (HR)-mediated DNA double strand break (DSB) repair, the subsequent persistence of DNA damage, and activation of the intrinsic apoptotic pathway. By generating a DSB repair deficiency, C225 can render head and neck tumor cells susceptible to PARP inhibition. The combination of C225 and the PARPi ABT-888 can thus be an innovative treatment strategy to potentially improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3166164
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2008). [gamma]H2AX and cancer.
  2. (1972). A new human cell line (FaDu) from a hypopharyngeal carcinoma.
  3. (2009). A selective eradication of human nonhereditary breast cancer cells by phenanthridine-derived polyADP-ribose polymerase inhibitors.
  4. (2007). ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNADamaging Agents in Preclinical Tumor Models.
  5. (2010). AC480, formerly BMS-599626, a pan Her inhibitor, enhances radiosensitivity and radioresponse of head and neck squamous cell carcinoma cells in vitro and in vivo. Invest New Drugs.
  6. (1985). An in vivo model for squamous cell carcinoma of the head and neck.
  7. (2002). Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks.
  8. (2004). Cell death: critical control points.
  9. (2010). Cetuximab-Based Immunotherapy and Radioimmunotherapy of Head and Neck Squamous Cell Carcinoma.
  10. (1999). Combined modality therapy of A431 human epidermoid cancer using antiEGFr antibody C225 and radiation.
  11. (2010). DNA Damage Induced Cytotoxicity Is Dissociated from BRCA1’s DNA Repair Function but Is Dependent on Its Cytosolic Accumulation.
  12. (2004). DNA Damage Induces p53-dependent BRCA1 Nuclear Export.
  13. (2010). EGFR inhibitor C225 increases the radiosensitivity of human lung squamous cancer cells.
  14. (2000). Enhanced Apoptosis With Combination C225/Radiation Treatment Serves as the Impetus for Clinical Investigation in Head and Neck Cancers.
  15. (1997). Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials.
  16. (2008). Erlotinib attenuates homologous recombinational repair of chromosomal breaks in human breast cancer cells.
  17. (2010). Genotyping of 73 UM-SCC head and neck squamous cell carcinoma cell lines.
  18. (2008). High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.
  19. (2002). Human papillomavirus and p53 mutational status as prognostic factors in head and neck carcinoma.
  20. (2010). Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. New England
  21. (2002). Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma.
  22. (2008). Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial.
  23. (2006). Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas.
  24. (1997). Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase.
  25. (2006). Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair.
  26. (2010). Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130.
  27. (2007). Inhibition of Poly(ADP-Ribose) Polymerase Enhances Cell Death and Improves Tumor Growth Delay in Irradiated Lung Cancer Models.
  28. (2009). Inhibition of poly(ADPribose) polymerase in tumors from BRCA mutation carriers.
  29. (2009). Lithium-mediated protection of hippocampal cells involves enhancement of DNA-PK-dependent repair in mice.
  30. (2003). Mechanism and regulation of human non-homologous DNA end-joining.
  31. (2005). Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva).
  32. (2000). Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of Enhanced Cytotoxicity with Cetuximab and ABT-888
  33. (2010). Nuclear EGFR shuttling induced by ionizing radiation is regulated by phosphorylation at residue Thr654.
  34. (1998). Physical Interaction between Epidermal Growth Factor Receptor and DNAdependent Protein Kinase in Mammalian Cells.
  35. (2010). Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors.
  36. (2009). Prosurvival AKT and ERK signaling from EGFR and mutant EGFRvIII enhances DNA double-strand break repair in human glioma cells.
  37. (2007). Radiation-induced EGFRsignaling and control of DNA-damage repair.
  38. (2005). Radiation-induced Epidermal Growth Factor Receptor Nuclear Import Is Linked to Activation of DNA-dependent Protein Kinase.
  39. (2010). Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
  40. (2006). Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.
  41. (2007). Response to therapy and outcomes in oropharyngeal cancer are associated with biomarkers including human papillomavirus, epidermal growth factor receptor, gender, and smoking.
  42. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
  43. (2009). The DNA-damage response in human biology and disease.