Identification of DNA repair pathways that affect the survival of ovarian cancer cells treated with a poly(ADP-ribose) polymerase inhibitor in a novel drug combination

• Published in: Molecular pharmacology Vol. 82; no. 4; pp. 767 - 776
• Main Authors: Huehls, Amelia M, Wagner, Jill M, Huntoon, Catherine J, Karnitz, Larry M
• Format: Journal Article
• Language: English
• Published: United States The American Society for Pharmacology and Experimental Therapeutics 01.10.2012
• Subjects: Antineoplastic Agents - pharmacology; Ataxia Telangiectasia Mutated Proteins; Benzimidazoles - pharmacology; Cell Cycle Checkpoints; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Checkpoint Kinase 1; Checkpoint Kinase 2; DNA Damage; DNA Repair; Drug Synergism; Enzyme Activation; Female; Floxuridine - pharmacology; Homologous Recombination; Humans; Ovarian Neoplasms - pathology; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Signal Transduction
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.112.080614

Floxuridine (5-fluorodeoxyuridine, FdUrd), a U.S. Food and Drug Administration-approved drug and metabolite of 5-fluorouracil, causes DNA damage that is repaired by base excision repair (BER). Thus, 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 (veliparib) alone, FdUrd alone, and FdUrd + ABT-888 (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. Taken together, 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 cells 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 compared with other chemotherapy + ABT-888 combinations, including cisplatin + ABT-888.