Resistance to therapy caused by intragenic deletion in BRCA2

Edwards, Stacey L., Brough, Rachel, Lord, Christopher J., Natrajan, Rachael, Vatcheva, Radost, Levine, Douglas A., Boyd, Jeff, Reis, Jorge S. and Ashworth, Alan (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature, 451 7182: 1111-1115. doi:10.1038/nature06548


Author Edwards, Stacey L.
Brough, Rachel
Lord, Christopher J.
Natrajan, Rachael
Vatcheva, Radost
Levine, Douglas A.
Boyd, Jeff
Reis, Jorge S.
Ashworth, Alan
Title Resistance to therapy caused by intragenic deletion in BRCA2
Formatted title
Resistance to therapy caused by intragenic deletion in BRCA2
Journal name Nature   Check publisher's open access policy
ISSN 0028-0836
1476-4687
Publication date 2008-02-28
Sub-type Article (original research)
DOI 10.1038/nature06548
Volume 451
Issue 7182
Start page 1111
End page 1115
Total pages 5
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted abstract
Cells with loss of BRCA2 function are defective in homologous recombination (HR) and are highly sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP), which provides the basis for a new therapeutic approach. Here we show that resistance to PARP inhibition can be acquired by deletion of a mutation in BRCA2. We derived PARP-inhibitor-resistant (PIR) clones from the human CAPAN1 pancreatic cancer cell line, which carries the protein-truncating c.6174delT frameshift mutation. PIR clones could form DNA-damage-induced RAD51 nuclear foci and were able to limit genotoxin-induced genomic instability, both hallmarks of a competent HR pathway. New BRCA2 isoforms were expressed in the resistant lines as a result of intragenic deletion of the c.6174delT mutation and restoration of the open reading frame (ORF). Reconstitution of BRCA2-deficient cells with these revertant BRCA2 alleles rescued PARP inhibitor sensitivity and HR deficiency. Most of the deletions in BRCA2 were associated with small tracts of homology, and possibly arose from error-prone repair caused by BRCA2 deficiency. Similar ORF-restoring mutations were present in carboplatin- resistant ovarian tumours from c.6174delT mutation carriers. These observations have implications for understanding drug resistance in BRCA mutation carriers as well as in defining functionally important domains within BRCA2.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ
Additional Notes Published under Letters

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Chemistry and Molecular Biosciences
 
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Created: Tue, 15 Mar 2011, 17:47:34 EST