Abstract
Checkpoint kinase 1 (ChK1) is a serine/threonine kinase that functions as a central mediator of the intra-S and G2-M cell-cycle checkpoints. Following DNA damage or replication stress, ChK1-mediated phosphorylation of downstream effectors delays cell-cycle progression so that the damaged genome can be repaired. As a therapeutic strategy, inhibition of ChK1 should potentiate the antitumor effect of chemotherapeutic agents by inactivating the postreplication checkpoint, causing premature entry into mitosis with damaged DNA resulting in mitotic catastrophe. Here, we describe the characterization of GNE-900, an ATP-competitive, selective, and orally bioavailable ChK1 inhibitor. In combination with chemotherapeutic agents, GNE-900 sustains ATR/ATM signaling, enhances DNA damage, and induces apoptotic cell death. The kinetics of checkpoint abrogation seems to be more rapid in p53-mutant cells, resulting in premature mitotic entry and/or accelerated cell death. Importantly, we show that GNE-900 has little single-agent activity in the absence of chemotherapy and does not grossly potentiate the cytotoxicity of gemcitabine in normal bone marrow cells. In vivo scheduling studies show that optimal administration of the ChK1 inhibitor requires a defined lag between gemcitabine and GNE-900 administration. On the refined combination treatment schedule, gemcitabine's antitumor activity against chemotolerant xenografts is significantly enhanced and dose-dependent exacerbation of DNA damage correlates with extent of tumor growth inhibition. In summary, we show that in vivo potentiation of gemcitabine activity is mechanism based, with optimal efficacy observed when S-phase arrest and release is followed by checkpoint abrogation with a ChK1 inhibitor.
Highlights
Chemotherapeutic agents that induce cytotoxicity by DNA damage have been among the most common cancer treatments since the pioneering use of nitrogen mustards in the 1940s
We have found that a 24-hour post-gemcitabine Checkpoint kinase 1 (ChK1) inhibitor regimen is broadly effective (e.g., MiaPaca2, MX-1, and SKOV-3; data not shown), depending on the pharmacogenomics of gemcitabine metabolism and response, optimal efficacy in other xenograft models might be achieved with shorter or longer lag times following gemcitabine treatment
Targeted chemopotentiation with ChK1 inhibitors represents a novel strategy to boost the efficacy of chemotherapeutic agents while maintaining the therapeutic index [37]
Summary
Chemotherapeutic agents that induce cytotoxicity by DNA damage have been among the most common cancer treatments since the pioneering use of nitrogen mustards in the 1940s. Despite their broad clinical application, there are significant limitations to the use of DNA-damaging agents. Cells respond to DNA damage and/or aberrant replication stress by activating cell-cycle checkpoints, slowing cell-cycle progression to facilitate DNA repair, or to promote death of cells with irreparable DNA lesions [5] Because these checkpoints play an important role in the response and resistance of tumor cells to chemotherapy, inhibitors of checkpoint mechanisms have been predicted to improve the efficacy of DNA-damaging agents
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