Targeting DDR with Anticancer Therapy

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The efficacy of PARP inhibitors in BRCA-deficient cancers highlights the potential of exploiting other DDR deficiencies to help overcome resistance to current therapies [1]. Two classes of DDR molecules are mainly being targeted for cytotoxic drug development: DNA damage signalling molecules and effector proteins for DNA repair [1].

DNA damage sensing proteins (e.g. ATM, ATR, DNA-PKcs, CHK1, CHK2 and WEE1) are protein kinases that respond to different types of DNA damage and/or regulate specific cell cycle transitions.

  • ATM is recruited to double-strand breaks and executes checkpoint signalling.
  • ATR is activated upon replication stress where it facilitates fork stabilisation and restart.
  • CHK1 and CHK2 are effector kinases that function downstream of ATR and ATM, respectively.
  • DNA-PKs are also recruited to double-strand breaks and execute DNA repair.
  • WEE1 is a classical checkpoint kinase that negatively regulates entry into mitosis. 

DNA repair proteins (PolQ, RAD51, PARG)

  • RAD51 and POLQ are directly involved in the double-strand break repair processes of HRR and MMEJ, respectively.
  • PARG is an enzyme that catabolises poly(ADP)ribose chains generated by the PARP family of enzymes.

References

  1. 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