The Elephant and the Blind Men: Making Sense of PARP Inhibitors in Homologous Recombination Deficient Tumor Cells.
Poly(ADP-ribose) polymerase 1 (PARP1) is an important component of the base excision repair (BER) pathway as well as a regulator of homologous recombination (HR) and non-homologous end-joining (NHEJ). Previous studies have demonstrated that treatment of HR-deficient cells with PARP inhibitors results in stalled and collapsed replication forks. Consequently, HR-deficient cells are extremely sensitive to PARP inhibitors. Several explanations have been advanced to explain this so-called synthetic lethality between HR deficiency and PARP inhibition: (i) reduction of BER activity leading to enhanced DNA double-strand breaks, which accumulate in the absence of HR; (ii) trapping of inhibited PARP1 at sites of DNA damage, which prevents access of other repair proteins; (iii) failure to initiate HR by poly(ADP-ribose) polymer-dependent BRCA1 recruitment; and (iv) activation of the NHEJ pathway, which selectively induces error-prone repair in HR-deficient cells. Here we review evidence regarding these various explanations for the ability of PARP inhibitors to selectively kill HR-deficient cancer cells and discuss their potential implications.
Division of Oncology Research, Mayo Clinic , Rochester, MN , USA.
Silvana B
SB
De Lorenzo
Anand G
AG
Patel
Rachel M
RM
Hurley
Scott H
SH
Kaufmann
BRCA1; BRCA2; PARP inhibitor; breast cancer; homologous recombination; non-homologous end joining; ovarian cancer; synthetic lethality