Inhibition of checkpoint kinases, an innovative strategy for treating advanced bladder cancer: Beyond the Abstract
In the present study, we developed a novel combination treatment killing bladder cancer cells by using AZD7762, an ATP-competitive inhibitor of checkpoint kinases 1 and 2 (CHK1 and CHK2), and the ribonucleotide reductase inhibitor gemcitabine. This study showed that CHK inhibition potentiates the cytotoxicity of gemcitabine selectively in bladder cancer cells. We think the reasons for this selectivity may include differences in checkpoint function and p53 regulation between normal cells and cancer cells. Upon DNA damage caused by gemcitabine, checkpoints respond to DNA damage by arresting the cell cycle to provide time for DNA repair. Tumor cells harboring defects in p53 function lack an efficient G1 checkpoint and thus have to rely on the S or G2 checkpoints for DNA repair, in which CHK1 and CHK2 have crucial functions [3, 4]. Checkpoint abrogation can therefore promote DNA-damage-induced mitotic catastrophe and cell death in p53-defective tumor cells [5], whereas normal cells may tolerate DNA damage stress by activating the G1 checkpoint through normal p53 function [3, 6].
We have found that the effect of AZD7762 is associated with abrogation of the G2 checkpoint activation induced by gemcitabine and with persistence of unrepaired DNA damage, as indicated by our findings that AZD7762 increased ataxia telangiectasia and RAD3-related (ATR)-mediated CHK1 phosphorylation (Ser345) and that it inhibited the repair of gemcitabine-induced double strand breaks as evidenced by sustained expression of γH2A.X and 53-BP1.
Thus the combination of gemcitabine and AZD7762 was effective against urothelial carcinoma cells. Unfortunately, a phase I clinical trial of AZD7762 conducted in patients with solid tumors other than bladder cancer was terminated prematurely because of cardiac toxicity [8]. Our study suggests that in the combination with gemcitabine inhibition of CHK1 alone, which may be less toxic, may suffice to treat bladder cancer. Indeed, other inhibitors specific for CHK1 or with broader target specificity are currently being tested in several clinical trials [9, 10], and the efficacy of combinations of gemcitabine and such agents in bladder cancer cells is under investigation in our laboratory.
Written By: Makoto Isono, MD, Department of Urology, National Defense Medical College, Tokorozawa, Japan
References:
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