Pharmacological Abrogation of S-Phase Checkpoint Enhances the Anti-Tumor Activity of Gemcitabine In Vivo

David J. Matthews, Michael Yakes, Jason Chen, Michele Tadano, Lester Bornheim, Douglas O. Clary, Albert Tai, Jill M. Wagner, Nicole Miller, Yong D. Kim, Scott Robertson, Louis Murray and Larry M. Karnitz

volume 6 | issue 1

1 January 2007
Pages: 104 - 110

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Chk1 and Chk2 kinases are critically involved in modulating DNA damage checkpoints. In particular, Chk1, a key activator of the S-phase DNA damage response, may be involved in resistance to genotoxic therapies that target DNA synthesis. We studied the in vitro and in vivo effects of EXEL-9844 (XL844), a potent, orally available, and specific inhibitor of Chk1 and Chk2, in combination with gemcitabine. In clonogenic assays using multiple cell lines in vitro, EXEL-9844 had only minor effects as a single agent but substantially enhanced gemcitabine-induced cell killing. Correspondingly, in PANC-1 cells, EXEL-9844 increased gemcitabine-induced H2AX phosphorylation, blocked Cdc25A phosphorylation, and induced premature mitotic entry. In a PANC-1 xenograft model, EXEL-9844 significantly enhanced gemcitabine antitumor activity but had limited effect as a single agent. Together, these data show that cell cycle checkpoint inhibitors may have significant clinical utility in potentiating the activity of gemcitabine.