Endogenous Replication Stress Marks Melanomas Sensitive to CHEK1 Inhibitors In Vivo
Purpose: Checkpoint kinase 1 inhibitors (CHEK1i) have single-agent activity in vitro as well as in vivo Here, we’ve investigated the molecular foundation of this activity.
Experimental Design: We’ve assessed a panel of melanoma cell lines for his or her sensitivity towards the CHEK1i GNE-323 and GDC-0575 in vitro as well as in vivo The results of those compounds on responses to DNA replication stress were examined within the sensitive cell lines.
Results: A subset of melanoma cell lines is sensitive to CHEK1i-caused cell dying in vitro, and also the drug effectively inhibits tumor development in vivo Within the sensitive cell lines, GNE-323 triggers cell dying without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyperphosphorylation and elevated DNA damage in just sensitive cells. The elevated replication stress was connected having a defective S-phase cell-cycle checkpoint. The amount and concentration of pRPA2 Ser4/8 foci in untreated tumors made an appearance to become a marker of elevated replication stress correlated with sensitivity to CHEK1i.
Conclusions: CHEK1i have single-agent activity inside a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly elevated this replication stress and DNA damage, which correlated ARRY-575 with elevated cell dying. The amount of endogenous replication is marked through the pRPA2Ser4/8 foci within the untreated tumors, and can be a helpful marker of replication stress