Targeting the Checkpoint to Kill Cancer Cells

Abstract

Cancer treatments such as radiotherapy and most of the chemotherapies act by damaging DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Inhibiting the checkpoint allows entry to mitosis despite the presence of DNA damage and can lead to cell death. Importantly, as cancer cells exhibit increased levels of endogenous DNA damage due to an excessive replication stress, inhibiting the checkpoint kinases alone could act as a directed anti-cancer therapy. Here, we review the current status of inhibitors targeted towards the checkpoint effectors and discuss mechanisms of their actions in killing of cancer cells.

Keywords: ATM; ATR; Chk1; DNA damage response; Wee1; cancer; checkpoint; inhibitor; p53; replication stress.

Figure 1

DNA damage response activates cell cycle checkpoint. Cell cycle progression is controlled by CDKs that are inactivated by Wee1 kinase and activated by Cdc25A/B/C phosphatases. Induction of DSBs activates ATM/Chk2 pathway, while exposed ssDNA initiates the ATR/Chk1 pathway. Both pathways inactivate Cdc25A/B/C leading to a temporal cell cycle arrest. Activation of p53/p21 pathway is crucial for the G1 checkpoint. The activation of the p38MAPK/MK2 pathway contributes to the checkpoint activation and maintenance.

Figure 2

Sensitizing cancer cells to DNA-damaging agents with checkpoint inhibitors. Cancer cells deficient in p53 lack G1 checkpoint and depend on checkpoint kinases to establish G2/M checkpoint. Inhibition of checkpoint kinases in combination with DNA damaging therapy leads to the G2/M checkpoint abrogation, mitotic catastrophe and cell death. Notably, healthy cells are protected by p53-dependent response.

Figure 2

Sensitizing cancer cells to DNA-damaging agents with checkpoint inhibitors. Cancer cells deficient in p53 lack G1 checkpoint and depend on checkpoint kinases to establish G2/M checkpoint. Inhibition of checkpoint kinases in combination with DNA damaging therapy leads to the G2/M checkpoint abrogation, mitotic catastrophe and cell death. Notably, healthy cells are protected by p53-dependent response.

Figure 3

Exploiting the addiction of cancer cells to ATR-Chk1-Wee1 signaling. The activation of oncogenes results in increased CDK activity, hyper-replication, and replication stress. Stalled forks are converted to DSBs. ATR/Chk1/Wee1 kinases oppose CDK2 activation and protect cells from the excessive replication stress. Chk1 and Wee1 protect cells from DNA damage by promoting homologous recombination (HR). Inhibition of ATR/Chk1/Wee1 kinases in cancer cells leads to excessive DNA damage and cell death.

Figure 4

Targeting the weak spots in individual tumors. Individual tumors exhibit various genetic backgrounds and thus have different weak spots. Single targeted therapy can never be efficient in all possible tumor variants. Therefore there is a great need to introduce diagnostic approaches that would, firstly, identify the weak spots of the particular tumor and then choose the effective targeted therapy.