title: Targeting cancer with a lupus autoantibody.
abstract: Systemic lupus erythematosus (SLE) is distinct among autoimmune diseases because of its association with circulating autoantibodies reactive against host DNA. The precise role that anti-DNA antibodies play in SLE pathophysiology remains to be elucidated, and potential applications of lupus autoantibodies in cancer therapy have not previously been explored. We report the unexpected finding that a cell-penetrating lupus autoantibody, 3E10, has potential as a targeted therapy for DNA repair-deficient malignancies. We find that 3E10 preferentially binds DNA single-strand tails, inhibits key steps in DNA single-strand and double-strand break repair, and sensitizes cultured tumor cells and human tumor xenografts to DNA-damaging therapy, including doxorubicin and radiation. Moreover, we demonstrate that 3E10 alone is synthetically lethal to BRCA2-deficient human cancer cells and selectively sensitizes such cells to low-dose doxorubicin. Our results establish an approach to cancer therapy that we expect will be particularly applicable to BRCA2-related malignancies such as breast, ovarian, and prostate cancers. In addition, our findings raise the possibility that lupus autoantibodies may be partly responsible for the intrinsic deficiencies in DNA repair and the unexpectedly low rates of breast, ovarian, and prostate cancers observed in SLE patients. In summary, this study provides the basis for the potential use of a lupus anti-DNA antibody in cancer therapy and identifies lupus autoantibodies as a potentially rich source of therapeutic agents.
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. james.e.hansen@yale.edu
authors.forename: James E
authors.initials: JE
authors.lastname: Hansen
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Liu
authors.forename: Denise C
authors.initials: DC
authors.lastname: Hegan
authors.forename: Shibani
authors.initials: S
authors.lastname: Dalal
authors.forename: Eloise
authors.initials: E
authors.lastname: Dray
authors.forename: Youngho
authors.initials: Y
authors.lastname: Kwon
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Peterson-Roth
authors.forename: Erik
authors.initials: E
authors.lastname: Geiger
authors.forename: Yilun
authors.initials: Y
authors.lastname: Liu
authors.forename: Joseph
authors.initials: J
authors.lastname: Gera
authors.forename: Joann B
authors.initials: JB
authors.lastname: Sweasy
authors.forename: Patrick
authors.initials: P
authors.lastname: Sung
authors.forename: Sara
authors.initials: S
authors.lastname: Rockwell
authors.forename: Robert N
authors.initials: RN
authors.lastname: Nishimura
authors.forename: Richard H
authors.initials: RH
authors.lastname: Weisbart
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D024682:BRCA2 Protein / Q000172:deficiency / Q000378:metabolism; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004277:DNA, Single-Stranded / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005910:Glioma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011485:Protein Binding; D057127:Single-Chain Antibodies / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001323:Autoantibodies; D024682:BRCA2 Protein; D004277:DNA, Single-Stranded; D057127:Single-Chain Antibodies