Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G 1 checkpoint‐defective neuroblastoma

Checkpoint kinase inhibitors can enhance the cancer killing action of DNA‐damaging chemotherapeutic agents by disrupting the S/G 2 cell cycle checkpoints. The in vitro and in vivo effects of the Chk1/2 inhibitor AZD7762 when combined with these agents were examined using neuroblastoma cell lines with known p53/MDM2/p14 ARF genomic status. Four of four p53 mutant lines and three of five MDM2/p14 ARF abnormal lines were defective in G 1 checkpoint, correlating with failure to induce endogenous p21 after treatment with DNA‐damaging agents. In cytotoxicity assays, these G 1 checkpoint‐defective lines were more resistant to DNA‐damaging agents when compared to G 1 checkpoint intact lines, yet becoming more sensitive when AZD7762 was added. Moreover, AZD7762 abrogated DNA damage‐induced S/G 2 checkpoint arrest both in vitro and in vivo . In xenograft models, a significant delay in tumor growth accompanied by histological evidence of increased apoptosis was observed, when AZD7762 was added to the DNA‐damaging drug gemcitabine. These results suggest a therapeutic potential of combination therapy using checkpoint kinase inhibitor and chemotherapy to reverse or prevent drug resistance in treating neuroblastomas with defective G 1 checkpoints.