PMID- 18264088
OWN - NLM
STAT- MEDLINE
DCOM- 20080331
LR  - 20220224
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Linking)
VI  - 451
IP  - 7182
DP  - 2008 Feb 28
TI  - Resistance to therapy caused by intragenic deletion in BRCA2.
PG  - 1111-5
LID - 10.1038/nature06548 [doi]
AB  - 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.
FAU - Edwards, Stacey L
AU  - Edwards SL
AD  - The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 
      Fulham Road, London SW3 6JB, UK.
FAU - Brough, Rachel
AU  - Brough R
FAU - Lord, Christopher J
AU  - Lord CJ
FAU - Natrajan, Rachael
AU  - Natrajan R
FAU - Vatcheva, Radost
AU  - Vatcheva R
FAU - Levine, Douglas A
AU  - Levine DA
FAU - Boyd, Jeff
AU  - Boyd J
FAU - Reis-Filho, Jorge S
AU  - Reis-Filho JS
FAU - Ashworth, Alan
AU  - Ashworth A
LA  - eng
GR  - A8363/CRUK_/Cancer Research UK/United Kingdom
GR  - BREAST CANCER NOW RESEARCH CENTRE/BCN_/Breast Cancer Now/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080210
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (BRCA2 Protein)
RN  - 0 (Fluorobenzenes)
RN  - 0 (KU0058948)
RN  - 0 (Phthalazines)
RN  - 0 (Poly(ADP-ribose) Polymerase Inhibitors)
RN  - 50SG953SK6 (Mitomycin)
RN  - BG3F62OND5 (Carboplatin)
SB  - IM
CIN - Nature. 2008 Feb 28;451(7182):1066-7. PMID: 18305536
MH  - Aged
MH  - Alleles
MH  - Amino Acid Sequence
MH  - BRCA2 Protein/deficiency/genetics
MH  - Base Sequence
MH  - Carboplatin/pharmacology
MH  - Cell Line, Tumor
MH  - Chromosome Aberrations/chemically induced
MH  - Drug Resistance, Neoplasm/*drug effects/*genetics
MH  - Female
MH  - Fluorobenzenes/pharmacology
MH  - Gene Expression Regulation, Neoplastic
MH  - *Genes, BRCA2
MH  - Humans
MH  - Middle Aged
MH  - Mitomycin/pharmacology
MH  - Molecular Sequence Data
MH  - Mutation/genetics
MH  - Open Reading Frames/genetics
MH  - Ovarian Neoplasms/drug therapy/genetics
MH  - Pancreatic Neoplasms/drug therapy/genetics/pathology
MH  - Phthalazines/pharmacology
MH  - Poly(ADP-ribose) Polymerase Inhibitors
MH  - Recombination, Genetic/genetics
MH  - Sequence Deletion/*genetics
EDAT- 2008/02/12 09:00
MHDA- 2008/04/01 09:00
CRDT- 2008/02/12 09:00
PHST- 2007/07/05 00:00 [received]
PHST- 2007/12/10 00:00 [accepted]
PHST- 2008/02/12 09:00 [pubmed]
PHST- 2008/04/01 09:00 [medline]
PHST- 2008/02/12 09:00 [entrez]
AID - nature06548 [pii]
AID - 10.1038/nature06548 [doi]
PST - ppublish
SO  - Nature. 2008 Feb 28;451(7182):1111-5. doi: 10.1038/nature06548. Epub 2008 Feb 10.