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The major obstacle in platinum chemotherapy is the repair of platinum-damaged DNA that results in increased resistance, reduced apoptosis and, finally, treatment failure.Our research goal is to determine and block the mechanisms of platinum resistance.Our recent studies demonstrate that several kinases in the DNA-repair pathway are activated after cells are exposed to cisplatin.These include ATM, p53, and Chk2.The increased Chk2-phosphorylation is modulated by p53 in a wild-type p53 model.Overexpression of p53 by cDNA transfection in wt-p53 (but not p53 deficient) cells doubled the amount of Chk2 phosphorylation 48-hour after cisplatin treatment.p53 knock-down by specific siRNA greatly reduced Chk2 phosphorylation.Inhibition of Chk2 pathway with a Chk2-inhibitor (C3742) increased cisplatin efficacy, especially those with defective p53.Our findings suggest that inhibition of platinum resistance can be achieved with a small-molecule inhibitor of Chk2, thus improving the therapeutic indices for platinum chemotherapy.