New Insights into Checkpoint Kinase 1 (Chk1) in the DNA Damage Response (DDR) Signaling Network: Rationale for Employing Chk1 Inhibitors in Cancer Therapeutics

摘要

The DNA damage response (DDR) represents a complex network of multiple signaling pathways involving cell cycle checkpoints, DNA repair, transcriptional programs, and apoptosis, through which cells maintain genomic integrity following various endogenous (metabolic) or environmental stresses. In cancer treatment, the DDR occurs in response to various genotoxic insults by diverse cytotoxic agents and radiation, representing an important mechanism limiting chemo- and radio-therapeutic efficacy. This has prompted the development of agents targeting DDR signaling pathways, particularly checkpoint kinase 1 (Chk1), which contributes to all currently defined cell cycle checkpoints, including G1/S, intra-S phase, G2/M, and the mitotic spindle checkpoint. While numerous agents have been developed with the primary goal of enhancing the activity of DNA-damaging agents or radiation, the therapeutic outcome of this strategy remains to be determined. Recently, new insights into DDR signaling pathways support the notion that Chk1 represents a core component central to the entire DDR, including, in addition to checkpoint regulation, direct involvement in DNA repair and apoptotic events. Together, these new insights into the role of Chk1 in the DDR machinery could provide an opportunity for novel approaches to the development of Chk1 inhibitor strategies.