Cell Cycle and DDR Targeting

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The DDR integrates the regulation of cell cycle progression with DNA repair, which allows time for repair and prevents DNA damage being permanently passed to daughter cells [1-3]. There are three checkpoints (G1/S, S phase, and G2/M) where the cell cycle may arrest in response to DNA damage (see the figure below) [1, 2, 4]. Accordingly, the specific proteins associated with each checkpoint are being targeted by small molecule inhibitors. These DDR-targeting agents aim to either maximise DNA damage in the G1 and S phases of the cell cycle or to prevent repair in G2, in order to ensure that the maximum amount of DNA damage is taken into mitosis.

Figure 6: Cell Cycle and DDR targeting [4]

Figure 6: Cell Cycle and DDR targeting

The three key cell cycle checkpoints and associated proteins are being targeted by small molecule inhibitors in clinical trials (top, right-hand box). Because they are rapidly dividing, cancer cells have increased susceptibility to DNA damage that in turn may lead to: 1) replication catastrophe or apoptosis, or 2) mitotic catastrophe (double-strand breaks carried into mitosis).
Adapted from Gourley, et al., J Clin Oncol 2019

References

  1. O'Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell 2015; 60: 547-560.
  2. Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 2012; 12: 801-817.
  3. Gourley C, Balmaña J, Ledermann JA et al. Moving from PARP Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol in press.
  4. Gourley C, Balmana J, Ledermann JA et al. Moving from PARP Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol 2019; doi: 10.1200/JCO.1218.02050. [Epub ahead of print].
Last update: 25 July 2019