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