Chk1 is the major mediator of cell-cycle checkpoints in response to various forms of genotoxic stress. Although it was previously speculated that checkpoint abrogation due to Chk1 inhibition may potentiate the efficacy of
DNA-damaging agents through induction of mitotic catastrophe, there has not been direct evidence proving this process. Here, through both molecular marker and morphological analysis, we directly demonstrate that specific downregulation of Chk1 expression by Chk1
siRNA potentiates the cytotoxicities of
topoisomerase inhibitors through the induction of premature chromosomal condensation and mitotic catastrophe. More importantly, we discovered that the cellular
cyclin B1 level is the major determinant of the potentiation. We show that downregulation of
cyclin B1 leads to impairment of the induction of mitotic catastrophe and correspondingly a reduction of the potentiation ability of either Chk1
siRNA or a small molecule Chk1 inhibitor. More significantly, we have extended the study by examining a panel of 10
cancer cell-lines with different tissue origins for their endogenous levels of
cyclin B1 and the ability of a Chk1 inhibitor to sensitize the cells to
DNA-damaging agents. The cellular levels of
cyclin B1 positively correlate with the degrees of potentiation achieved. Of additional interest, we observed that the various
colon cancer cell lines in general appear to express higher levels of
cyclin B1 and also display higher sensitivity to Chk1 inhibitors, implying that Chk1 inhibitor may be more efficacious in treating
colon cancers. In summary, we propose that
cyclin B1 is a
biomarker predictive of the efficacy of Chk1 inhibitors across different types of
cancers. Unlike previously established efficacy-predictive
biomarkers that are usually the direct targets of the therapeutic agents,
cyclin B1 represents a non-
drug-target
biomarker that is based on the mechanism of action of the target inhibitor. This finding may be potentially very useful for the stratification of patients for Chk1 inhibitor clinical trials and hence, maximize its chance of success.