Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition
Vignesh Sundararajan 1, Tuan Zea Tan 1 2, Diana Lim 3, Yanfen Peng 1, Antje Margret Wengner 4, Natalie Yan Li Ngoi 5, Anand D Jeyasekharan 1, David Shao Peng Tan 1 5
Excessive genomic instability along with abnormalities in DNA repair pathways induces high amounts of ‘replication stress’ when cancer cells propagate. Instead of hampering cancer cell proliferation, novel treatment strategies are turning their attention towards targeting cell cycle checkpoint kinases (for example ATR, CHK1, WEE1, yet others) across the DNA damage response and replicative stress response pathways, therefore allowing unrepaired DNA harm to be transported forward towards mitotic catastrophe and apoptosis. The selective ATR kinase inhibitor elimusertib (BAY 1895344) has shown preclinical and clinical monotherapy activity however, reliable predictive biomarkers of treatment benefit continue to be missing. Within this study, using gene expression profiling of 24 cell lines from various cancer types as well as in a panel of ovarian cancer cell lines, we discovered that nuclear-specific enrichment of checkpoint kinase 1 (CHK1) correlated with elevated sensitivity to elimusertib. Utilizing an advanced multispectral imaging system in subsequent cell line-derived xenograft examples, we demonstrated a pattern between nuclear phosphorylated CHK1 (pCHK1) staining and elevated sensitivity towards the ATR inhibitor elimusertib, indicating the possibility worth of pCHK1 expression like a predictive biomarker of ATR inhibitor sensitivity. ? 2022 The Authors. The Journal of Pathology printed by John Wiley & Sons Limited with respect to The Pathological Society of effective Britain and Ireland.