title: Targeting aberrant DNA double-strand break repair in triple-negative breast cancer with alpha-particle emitter radiolabeled anti-EGFR antibody.
abstract: The higher potential efficacy of alpha-particle radiopharmaceutical therapy lies in the 3- to 8-fold greater relative biological effectiveness (RBE) of alpha particles relative to photon or beta-particle radiation. This greater RBE, however, also applies to normal tissue, thereby reducing the potential advantage of high RBE. As alpha particles typically cause DNA double-strand breaks (DSB), targeting tumors that are defective in DSB repair effectively increases the RBE, yielding a secondary, RBE-based differentiation between tumor and normal tissue that is complementary to conventional, receptor-mediated tumor targeting. In some triple-negative breast cancers (TNBC; ER(-)/PR(-)/HER-2(-)), germline mutation in BRCA-1, a key gene in homologous recombination DSB repair, predisposes patients to early onset of breast cancer. These patients have few treatment options once the cancer has metastasized. In this study, we investigated the efficacy of alpha-particle emitter, (213)Bi-labeled anti-EGF receptor antibody, cetuximab, in BRCA-1-defective TNBC. (213)Bi-cetuximab was found to be significantly more effective in the BRCA-1-mutated TNBC cell line HCC1937 than BRCA-1-competent TNBC cell MDA-MB-231. siRNA knockdown of BRCA-1 or DNA-dependent protein kinase, catalytic subunit (DNA-PKcs), a key gene in non-homologous end-joining DSB repair pathway, also sensitized TNBC cells to (213)Bi-cetuximab. Furthermore, the small-molecule inhibitor of DNA-PKcs, NU7441, sensitized BRCA-1-competent TNBC cells to alpha-particle radiation. Immunofluorescent staining of γ-H2AX foci and comet assay confirmed that enhanced RBE is caused by impaired DSB repair. These data offer a novel strategy for enhancing conventional receptor-mediated targeting with an additional, potentially synergistic radiobiological targeting that could be applied to TNBC.
authors.affiliation: Corresponding Author: George Sgouros, The Johns Hopkins University School of Medicine, Rm 4M61 Cancer Research Building II, 1550 Orleans Street, Baltimore, MD 21231. gsgouros@jhmi.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Song
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hedayati
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hobbs
authors.forename: Chunbo
authors.initials: C
authors.lastname: Shao
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: Theodore L
authors.initials: TL
authors.lastname: Deweese
authors.forename: George
authors.initials: G
authors.lastname: Sgouros
mesh_terms: D000512:Alpha Particles; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D019313:BRCA1 Protein / Q000235:genetics*; D001729:Bismuth / Q000008:administration & dosage; D045744:Cell Line, Tumor; D000068818:Cetuximab; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D059766:DNA End-Joining Repair / Q000187:drug effects / Q000276:immunology; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D011868:Radioisotopes / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C468783:H2AX protein, human; D006657:Histones; D011868:Radioisotopes; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; D001729:Bismuth