Targeting cancer with a lupus autoantibody

Hansen, J.E., Chan, G., Liu, Y., Hegan, D.C., Dalal, S., Dray, E., Kwon, Y., Xu, Y., Xu, X., Peterson-Roth, E., Geiger, E., Liu, Y., Gera, J., Sweasy, J.B., Sung, P., Rockwell, S., Nishimura, R.N., Weisbart, R.H., & M. Glazer, P. (2012) Targeting cancer with a lupus autoantibody. Science Translational Medicine, 4(157), 157ra142.

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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.

Impact and interest:

24 citations in Scopus
16 citations in Web of Science®
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ID Code: 73269
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after if you register
DOI: 10.1126/scitranslmed.3004385
ISSN: 1946-6242
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > MEDICAL BIOCHEMISTRY AND METABOLOMICS (110100)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > MEDICAL MICROBIOLOGY (110800)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 American Association for the Advancement of Science
Deposited On: 03 Jul 2014 01:26
Last Modified: 21 Jun 2017 20:01

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