BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of Poly (ADP-Ribose) polymerase: an issue of potency.
We have previously demonstrated that deficiency of either the BRCA1 or BRCA2 breast cancer susceptibility proteins confers substantial cellular sensitivity to the inhibition of Poly(ADP-Ribose) polymerase (PARP). PARP is a key enzyme in the repair of single strand DNA damage via the Base Excision Repair pathway. We suggested that PARP inhibition produces persistent single-strand DNA breaks or gaps which degenerate into stalled replication forks and double-strand breaks, which may be repaired by homologous recombination, a process partially dependent on BRCA1 and BRCA2. It has recently been suggested that our results might be limited to certain BRCA2 mutations as the CAPAN-1 cell line, which carries a naturally occurring 6174delT mutation in one BRCA2 allele accompanied by loss of the wild-type allele, is apparently insensitive to two PARP inhibitors 3-aminobenzamide (IC50 33 microM) and NU1025 (IC50 400 nM). Here we show that CAPAN-1 cells are in fact very sensitive to the potent PARP inhibitors KU0058684 (IC50 3.2 nM) and KU0058948 (IC50 3.4 nM). In contrast, our results reveal much less sensitivity to a chemically related but much less active compound KU0051529 (IC50 730 nM) and to NU1025. These results confirm that treatment with potent PARP inhibitors remains an exciting potential therapy for cancers involving BRCA1 or BRCA2 deficiency.
McCabe
Nuala
N
The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
Lord
Christopher J
CJ
Tutt
Andrew N J
AN
Martin
Niall M B
NM
Smith
Graeme C M
GC
Ashworth
Alan
A
D024682:BRCA2 Protein / Q000172:deficiency*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D024522:Genes, BRCA2; D006801:Humans; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000145:classification
D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases