Abstract
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.
Original language | English (US) |
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Pages (from-to) | 104-110 |
Number of pages | 7 |
Journal | Cell Cycle |
Volume | 6 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2007 |
Keywords
- CHK1
- CHK2
- EXEL-9844
- Gemcitabine
- S-phase checkpoint
- XL844
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology
- Cell Biology