Combination drug scheduling defines a "window of opportunity" for chemopotentiation of gemcitabine by an orally bioavailable, selective CHK1 inhibitor, GNE-900
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels un composé appelé GNE-900, un inhibiteur de la kinase ChK1, potentialise l'activité de la gemcitabine
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 anti-tumor effect of chemotherapeutic agents by inactivating the post-replication 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 appears to be more rapid in p53 mutant cells, resulting in premature mitotic entry and/or accelerated cell death. Importantly, we demonstrate 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 demonstrate 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 anti-tumor activity against chemo-tolerant xenografts is significantly enhanced and dose-dependent exacerbation of DNA damage correlates with extent of tumor growth inhibition. In summary, we demonstrate 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.
http://mct.aacrjournals.org/content/early/2013/07/19/1535-7163.MCT-12-1218.abstract