Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Abstract

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.

Targeting the ATR-CHK1 Axis in Cancer Therapy

“…AZD7762 potentiated the cytotoxicity of gemcitabine in a panel of NSCLC cell lines [74] and also in a panel of neuroblastoma cells lines [75]. In both cases sensitisation to gemcitabine was observed to be independent of their p53 status or G1 checkpoint proficiency and this observation is consistent with the demonstration that chemosensitisation by CHK1 knock down was not specific to p53 deficient cells [54].…”

“…The CHK1/2 inhibitor, AZD7762, potentiated topotecan cytotoxicity in G1 checkpoint defective neuroblastoma cell lines, but in contrast to the results seen in combination with gemcitabine, cell lines with an intact G1 checkpoint were not affected [75]. A 10-fold potentiation of topotecan was observed in high grade serous ovarian cancer cell lines when used in combination with PF477736 [83].…”

CASZ1 inhibits cell cycle progression in neuroblastoma by restoring pRb activity

“…6 In addition, Chk1 is highly expressed and/or constitutively phosphorylated in high-risk NB tumors, 7 with treatment with Chk1 inhibitors inducing cell death in vitro and delays in NB xenograft growth in vivo. 7,8 Human CASZ1 is a recently discovered tumor suppressor gene that maps to chromosome 1p36, whose deletion is a chromosomal anomaly implicated in NB tumorigenesis. 2,[9][10][11][12] Whether it has tumor suppressor activity in other cancers is still under investigation, but a case of cervical cancer has been reported in which human papillomavirus DNA integrated into the CASZ1 gene locus and disrupted its expression.…”

Molecularly Targeted Therapies in Non–Small-Cell Lung Cancer Annual Update 2014

“…Checkpoint kinase inhibitors disrupt the cancer cell's ability to repair this damage, and have recently shown promising activity as single agents in select patient populations and in combination with DNA-damaging therapies in broader tumor settings. 269, 270 Many of these novel agents are being developed in lung cancer treatment.…”