PARP inhibitors

Module 1

Poly (ADP-ribose) polymerase (PARP) comprises a family of 17 proteins, of which PARP1 and PARP2 are involved in intracellular DNA Damage Response (DDR) pathways, which sense DNA breakages and play a key role in their repair [1].

Several molecules that inhibit PARP1/PARP2 function have been developed. PARP inhibitors not only block the enzymatic activity of PARP, more importantly they trap PARP1 on the damaged DNA, resulting in stalled replication forks and subsequent formation of double-stranded breaks [2, 3]. In vitro data has shown that the clinical efficacy of PARP inhibitors is associated mostly with their PARP-trapping efficiency, and that mutations in PARP1 that affect its trapping can result in drug resistance [3, 4].

Further information on PARP activity and inhibition can be found by clicking on each topic below.

References

  1. Schreiber V, Dantzer F, Ame JC, de Murcia G. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 2006; 7: 517-528.
  2. 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].
  3. Murai J, Huang SY, Das BB et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 2012; 72: 5588-5599.
  4. Pettitt SJ, Krastev DB, Brandsma I et al. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun 2018; 9: 1849.