Abstract
Purpose: Checkpoint kinase 1 inhibitors (CHEK1i) have single-agent activity in vitro and in vivo Here, we have investigated the molecular basis of this activity.Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines.Results: A subset of melanoma cell lines is hypersensitive to CHEK1i-induced cell death in vitro, and the drug effectively inhibits tumor growth in vivo In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyperphosphorylation and increased DNA damage in only hypersensitive cells. The increased replication stress was associated with a defective S-phase cell-cycle checkpoint. The number and intensity of pRPA2 Ser4/8 foci in untreated tumors appeared to be a marker of elevated replication stress correlated with sensitivity to CHEK1i.Conclusions: CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated with increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumors, and may be a useful marker of replication stress in vivoClin Cancer Res; 24(12); 2901-12. ©2018 AACR.
Highlights
Cell-cycle checkpoints are potential therapeutic targets in melanoma [1]
A subset of melanoma cell lines is hypersensitive to CHEK1 inhibitors (CHEK1i)-induced cell death in vitro, and the drug effectively inhibits tumor growth in vivo
CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated with increased cell death
Summary
Cell-cycle checkpoints are potential therapeutic targets in melanoma [1]. CHEK1 is a cell-cycle checkpoint effector that is activated in response to DNA damage and replication stress to block cell-cycle progression and apoptosis, and regulate DNA replication and repair [2, 3]. It is activated in response to many chemotherapeutic agents, and inhibiting CHEK1 activity strongly enhances the potency of a range of chemotherapeutic drugs, drugs such as gemcitabine that enhance replication stress [4]. CHEK1 inhibitors (CHEK1i) are being investigated in clinical trials to enhance the efficacy of chemotherapeutic drugs, primarily gemcitabine [5, 6]. CHEK1i have been reported not to have broad activity as single agents, they have been shown to be potent anticancer agents in melanoma, Myc-driven lymphoma, and a small number of other cancer cell lines that have been reported.
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