Table 2.

Mechanisms of resistance to PARPi

ConstitutiveAcquired
Ras mutationReconstitution of HR
  • Healing of BRCA1/2, Rad51C, Rad51D

  • Demethylation of BRCA1/2 promoter

  • Upregulation of hypomorphic mutant BRCA1/2 allele

  • Loss of shield complex

GPB1 lossReplication fork protection
  • Loss of MLL3/4 or PTIP (MRE11 effector)

  • Loss of EZH2 (MUS81 effector)

  • Decreased proliferation

Other
  • Loss of PARP

  • PARP mutations

  • PARG-mediated reversal of ADP ribosylation of PARP

  • Overexpression and fusion of P glycoprotein/MDR/ABC transporters

  • Loss of SLFN11

  • EMT

  • Removal of ribonucleotides by ribonuclease H2