Targeting the ATR-CHK1 Axis in Cancer Therapy

Abstract

Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article describes the role of ATR and its major downstream target, CHK1, in the DDR and why cancer cells are particularly reliant on the ATR-CHK1 pathway, providing the rationale for targeting these kinases, and validation of this hypothesis by genetic manipulation. The recent development of specific inhibitors and preclinical data using these inhibitors not only as chemosensitisers and radiosensitisers but also as single agents to exploit specific pathologies of tumour cells is described. These potent and specific inhibitors have now entered clinical trial and early results are presented.

Withaferin A inhibits expression of ataxia telangiectasia and Rad3‐related kinase and enhances sensitivity of human breast cancer cells to cisplatin

“…High mRNA level of CHK1 was also shown to be associated with aggressive phenotype in breast cancer . Intense efforts are underway for clinical development of ATR and CHK1 inhibitors for treatment of cancers and for combination regimens with chemotherapy and radiation therapy . The present study shows downregulation of ATR and its activity inhibition reflected by suppression of CHK1 phosphorylation by WA treatment in breast cancer cells.…”

“…Moreover, Cdc25C overexpression in MDA‐MB‐231 cells resulted in partial but statistically significant attenuation of G 2 /M phase cell‐cycle arrest resulting from WA exposure . Interestingly, Cdc25C is a phosphorylation target of CHK1 . Phosphorylation of Cdc25C by CHK1 results in inhibition of Cdk1 activity and G 2 /M phase cell‐cycle arrest .…”

Characterization and drug sensitivity of a novel human ovarian clear cell carcinoma cell line genomically and phenotypically similar to the original tumor

“…It is not possible to make a direct comparison in terms of LC 50 values with many of those reported in other studies due to use of different treatment protocols and analysis methods. NUCOLL43 cells were slightly less sensitive to the ATR inhibitor VE‐821 as a single agent than breast cancer cells using a similar assay protocol and sensitization of cisplatin by VE‐821 appeared to be less than has been reported for other cell lines . Although NUCOLL43 cells were not sensitive to rucaparib as a single agent the radiopotentiation by rucaparib was about 1.8‐fold in NUCOLL43 cells, which is higher than we have observed in other cell lines using colony formation assays and similar exposure periods .…”

New strategies in ovarian cancer treatment

“…A series of cell cycle checkpoint inhibitors currently are under development or already in 10 These responses include activation of cell cycle checkpoints causing subsequent cell cycle arrest to provide the cell with time to repair damaged DNA, and activation of the appropriate DNA repair mechanisms to efficiently complete repair. A series of cell cycle checkpoint inhibitors currently are under development or already in 10 These responses include activation of cell cycle checkpoints causing subsequent cell cycle arrest to provide the cell with time to repair damaged DNA, and activation of the appropriate DNA repair mechanisms to efficiently complete repair.…”