title: Cetuximab augments cytotoxicity with poly (adp-ribose) polymerase inhibition in head and neck cancer.
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.
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America.
authors.forename: Somaira
authors.initials: S
authors.lastname: Nowsheen
authors.forename: James A
authors.initials: JA
authors.lastname: Bonner
authors.forename: Albert F
authors.initials: AF
authors.lastname: Lobuglio
authors.forename: Hoa
authors.initials: H
authors.lastname: Trummell
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Whitley
authors.forename: Michael C
authors.initials: MC
authors.lastname: Dobelbower
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D004249:DNA Damage; D059766:DNA End-Joining Repair / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006258:Head and Neck Neoplasms / Q000473:pathology*; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors; C521013:veliparib; D066246:ErbB Receptors; D000068818:Cetuximab