TABLE 1.

PARP inhibitor resistance mechanisms.

Resistance mechanism	Cause of resistance	Pre-clinical and clinical observations	References
HR restoration	BRAC1/2 Reversion restoring HR	Mutations in patient tumors and PDX models treated with PARPi, reversion mutations in BRCA1 and BRCA2 occur frequently in patients with PARPi-resistant cancers	Ter Brugge et al., 2016; Goodall et al., 2017
	Demethylation of hypermethylated BRCA1 promoter	PDX models treated with PARPi	Ter Brugge et al., 2016
	Loss of 53BP1	Low expression and mutations in BRCA1 deficient PDX models	Bouwman et al., 2010; Bunting et al., 2010
	Loss of Shieldin factors	Low expression and Mutations in BRCA1 deficient PDX model	Dev et al., 2018; Noordermeer et al., 2018
	Loss of CTC/Pola	In vitro observations that phenocopy 53BP1 loss	Mirman et al., 2018
	Loss of DYNLL1/ATMIN	In vitro reports that partially phenocopy 53BP1 loss	He et al., 2018
Stalled fork stabilization	Loss of PTIP, SLFN11 and SMARCAL1	In vitro reports of loss inducing PARPi resistance in BRCA1/2 deficient cells	Chaudhuri et al., 2016; Taglialatela et al., 2017; Murai et al., 2018
	Loss of EZH2	In vitro reports of loss inducing PARPi resistance in BRCA2 deficient cells	Rondinelli et al., 2017
Loss of PARP trapping	Mutation in PARP	In vitro reports of mutations in PARP that induce resistance in BRCA2 deficient cells, PARP1 mutation (R591C) which prevents trapping found in a de novo PARPi resistant patient tumor	Pettitt et al., 2018
	Loss of PARG	In vitro PARG depletion can cause PARPi resistance in BRCA2−/− background	Gogola et al., 2018
Increased drug efflux	ABC transporter upregulation	PARPi resistance in vitro and in mouse models	Rottenberg et al., 2008; Jaspers et al., 2013; Vaidyanathan et al., 2016