Identification of DNA Repair Pathways that Affect the Survival of Ovarian Cancer Cells Treated with a PARP Inhibitor in a Novel Drug Combination.

Publication Type:

Journal Article

Source:

Molecular pharmacology (2012)

Abstract:

Floxuridine (5-fluorodeoxyuridine, FdUrd), an FDA-approved drug and metabolite of 5-fluorouracil, causes DNA damage that is repaired by base excision repair (BER). Accordingly, poly(ADP-ribose) polymerase (PARP) inhibitors, which disrupt BER, markedly sensitize ovarian cancer cells to FdUrd, suggesting that this combination may have activity in this disease. It remains unclear, however, which DNA repair and checkpoint signaling pathways affect killing by these agents individually and in combination. Here we show that depleting ATR, BRCA1, BRCA2, or Rad51 sensitized to ABT-888 alone, FdUrd alone, and F+A, suggesting that homologous recombination (HR) repair protects cells exposed to these agents. In contrast, disabling the mismatch, nucleotide excision, Fanconi Anemia, nonhomologous end joining, or translesion synthesis repair pathways did not sensitize to these agents alone (including ABT-888) or in combination. Further studies demonstrated that in BRCA1-depleted cells, F+A was more effective than other chemotherapy+ABT-888 combinations. Collectively, these studies 1) identify DNA repair and checkpoint pathways that are important in ovarian cancer cells treated with FdUrd, ABT-888, and F+A; 2) show that disabling HR at the level of ATR, BRCA1, BRCA2, or Rad51 - but not Chk1, ATM, PTEN, or FANCD2 - sensitizes to ABT-888; and 3) demonstrate that even though ABT-888 sensitizes ovarian tumor cells with functional HR to FdUrd, the effects of this drug combination are more profound in tumors with HR defects, even when compared to other chemotherapy+ABT-888 combinations, including cisplatin+ABT-888.