Deficiency in the Repair of DNA Damage by Homologous Recombination and Sensitivity to Poly(ADP-Ribose) Polymerase Inhibition

TLDR

Deficiency of the breast cancer susceptibility proteins BRCA1 or BRCA2 makes cells highly sensitive to inhibition of poly(ADP‑ribose) polymerase (PARP). The study tested whether the essential role of BRCA1 and BRCA2 in homologous recombination repair explains their cells’ sensitivity to PARP inhibition. The authors examined how loss of various homologous recombination proteins affects cellular sensitivity to PARP inhibition. Deficiencies in multiple HR proteins—including RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, and FANCC—render cells highly sensitive to PARP inhibition, supporting the idea that HR deficiency underlies this vulnerability and indicating that PARP inhibitors could treat not only BRCA‑mutated cancers but also other tumors with HR pathway defects or BRCAness.

Abstract

Abstract Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of ‘BRCAness.’ (Cancer Res 2006; 66(16): 8109-15)