Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition

by Selleckchem | Aug 19 2023

Excessive genomic instability coupled with abnormalities in DNA repair pathways induces high levels of 'replication stress' when cancer cells propagate. Rather than hampering cancer cell proliferation, novel treatment strategies are turning their attention towards targeting cell cycle checkpoint kinases (such as ATR, CHK1, WEE1, and others) along the DNA damage response and replicative stress response pathways, thereby allowing unrepaired DNA damage to be carried forward towards mitotic catastrophe and apoptosis. The selective ATR kinase inhibitor elimusertib (BAY 1895344) has demonstrated preclinical and clinical monotherapy activity; however, reliable predictive biomarkers of treatment benefit are still lacking. In this study, using gene expression profiling of 24 cell lines from different cancer types and in a panel of ovarian cancer cell lines, we found that nuclear-specific enrichment of checkpoint kinase 1 (CHK1) correlated with increased sensitivity to elimusertib. Using an advanced multispectral imaging system in subsequent cell line-derived xenograft specimens, we showed a trend between nuclear phosphorylated CHK1 (pCHK1) staining and increased sensitivity to the ATR inhibitor elimusertib, indicating the potential value of pCHK1 expression as a predictive biomarker of ATR inhibitor sensitivity. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Comments:

The excerpt you provided describes the phenomenon of replication stress in cancer cells and the potential of targeting cell cycle checkpoint kinases as a treatment strategy. It specifically highlights the ATR kinase inhibitor elimusertib (BAY 1895344) as a promising therapeutic agent. The study mentioned in the excerpt investigated the correlation between the expression of checkpoint kinase 1 (CHK1) and the sensitivity to elimusertib in different cancer cell lines.

The researchers performed gene expression profiling in 24 cell lines from various cancer types, as well as a panel of ovarian cancer cell lines. They found that nuclear-specific enrichment of CHK1 was associated with increased sensitivity to elimusertib. To further validate these findings, the researchers employed a multispectral imaging system in cell line-derived xenograft specimens. They observed a trend indicating that higher levels of nuclear phosphorylated CHK1 (pCHK1) staining correlated with increased sensitivity to elimusertib. This suggests that the expression of pCHK1 may serve as a potential predictive biomarker for determining sensitivity to ATR inhibitors like elimusertib.

It is worth noting that the excerpt is a summary or abstract of a study published in The Journal of Pathology by The Pathological Society of Great Britain and Ireland in 2022. The complete study likely provides more detailed information about the experimental methods, results, and implications of these findings.