Table 1.

PARP inhibitor resistance mechanisms.

HR-dependent mechanisms	HR-independent mechanisms
BRCA-dependent HR restoration BRCA reversion mutation BRCA promotor demethylation Upregulation of hypomorphic BRCA mutations BRCA-independent HR restoration By loss of negative regulators for HR, e.g., 53BP1, RIP1, REV7, or SHLD complex By amplification of TRIP13 leading to removal of SHLD complex By reversion mutations of HR pathway genes, e.g., RAD51C, RAD51D, PALB2	Replication fork stabilization Loss of PTIP, MRE11, EZH2, TET2, APE1, decreased SLFN11 Upregulation of survival pathways/senescence PI3K/AKT, ATR/CHK1, Wnt signaling Others Losing target, e.g., PARP1 mutation Increased drug efflux (ABCB1/p-glycoprotein; ABCC2/MRP2; ABCG2/BCRP) Decrease in PARG, thus increasing PAR chains

Abbreviations; HR, homologous recombination; PAR, poly (ADP ribose); PARG, poly (ADP ribose) glycohydrolase.