title: A nucleolytic lupus autoantibody is toxic to BRCA2-deficient cancer cells.
abstract: Cancer cells with defects in DNA repair are highly susceptible to DNA-damaging agents, but delivery of therapeutic agents into cell nuclei can be challenging. A subset of lupus autoantibodies is associated with nucleolytic activity, and some of these antibodies are capable of nuclear penetration. We hypothesized that such antibodies might have potential as therapeutic agents targeted towards DNA repair-deficient malignancies. We identified the lupus autoantibody 5C6 as a cell-penetrating nucleolytic antibody and found that 5C6 has a differential effect on a matched pair of BRCA2-proficient and deficient DLD1 colon cancer cells. 5C6 selectively induced γH2AX in, and suppressed the growth of, the BRCA2-deficient cells. These findings demonstrate the potential utility of 5C6 in targeted therapy for DNA repair-deficient malignancies and strengthen the rationale for studies of additional lupus autoantibodies in order to identify the best candidates for development as therapeutic agents. In addition, the toxic effect of 5C6 on BRCA2-deficient cells provides further support for the hypothesis that some lupus autoantibodies contribute to the lower risk of specific cancers associated with systemic lupus erythematosus.
authors.affiliation: From the Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Noble
authors.affiliation: From the Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Young
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Sasha
authors.initials: S
authors.lastname: Bernatsky
authors.affiliation: Department of Research, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA 91343.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Weisbart
authors.affiliation: 1] From the Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520 [2] Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520.
authors.forename: James E
authors.initials: JE
authors.lastname: Hansen
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D024682:BRCA2 Protein / Q000172:deficiency* / Q000235:genetics; D001692:Biological Transport; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006825:Hybridomas / Q000737:chemistry / Q000276:immunology; D051379:Mice
chemical_list: D000974:Antibodies, Antinuclear; D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D057846:Cell-Penetrating Peptides; D004273:DNA, Neoplasm; C468783:H2AX protein, human; D006657:Histones
references.citation: Cancer Res. 2002 Mar 15;62(6):1876-83
references.pmid: 11912168
references.citation: Cancer Res. 2007 Feb 15;67(4):1769-74
references.pmid: 17308119
references.citation: J Mol Recognit. 2011 Jul-Aug;24(4):557-69
references.pmid: 20842640
references.citation: N Engl J Med. 2009 Oct 8;361(15):1475-85
references.pmid: 19812404
references.citation: J Immunol. 1998 Dec 15;161(12):6999-7006
references.pmid: 9862736
references.citation: Stroke. 2010 Mar;41(3):538-43
references.pmid: 20075343
references.citation: Ann Rheum Dis. 2008 Jan;67(1):74-9
references.pmid: 17545189
references.citation: Lupus. 2001;10(5):315-8
references.pmid: 11403260
references.citation: Bioorg Med Chem. 2007 Mar 1;15(5):2016-23
references.pmid: 17234421
references.citation: Lupus. 2012 Jul;21(8):896-9
references.pmid: 22495874
references.citation: J Immunol. 1995 Feb 15;154(4):1987-94
references.pmid: 7836777
references.citation: Br J Cancer. 2011 Apr 26;104(9):1478-81
references.pmid: 21487409
references.citation: Int J Cancer. 2011 Dec 15;129(12):2966-9
references.pmid: 21448902
references.citation: Sci Transl Med. 2012 Oct 24;4(157):157ra142
references.pmid: 23100628
references.citation: N Engl J Med. 2008 Feb 28;358(9):929-39
references.pmid: 18305268
references.citation: J Biol Chem. 2011 Oct 28;286(43):37813-29
references.pmid: 21878644
references.citation: J Autoimmun. 2013 May;42:130-5
references.pmid: 23410586
references.citation: Mech Ageing Dev. 2009 Jan-Feb;130(1-2):24-32
references.pmid: 18538372
references.citation: Hum Mol Genet. 2013 Apr 15;22(8):1525-38
references.pmid: 23307925
references.citation: Science. 1992 May 1;256(5057):665-7
references.pmid: 1585181