Table 1.
Proposed mechanisms of PARPi resistance.
| Resistance Mechanism | Evidence | References |
|---|---|---|
| Primary resistance | ||
| PI3K/AKT pathway activation | Cell lines | Yi et al. [31] |
| Wild-type PTEN | Cell lines | Dedes et al. [32] |
| Loss of NHEJ | Cell lines | Balmus et al. [33], Patel et al. [34], Mc Cormick et al. [35] |
| ALC1 overexpression | Cell lines | Juhász et al. [36] |
| Secondary resistance | ||
| Upregulation of ABC transporters | Mouse models, cell lines |
Jaspers et al. [37], Vaidyanathan et al. [38] |
| Decreased PARP1 trapping | Mouse models, cell lines |
Pettitt et al. [39], Gogola et al. [40] |
| Restoration of HR | ||
| -BRCA1/2 reversion mutations | Tumour DNA and ctDNA from cancer patients | Tobalina et al. [41] |
| -Hypomorphic BRCA1 allele | Cell lines, mouse models, PDXs | Drost et al. [42], Wang et al. [43], Cruz et al. [44], Wang et al. [45], Castroviejo-Bermejo et al. [46] |
| -Loss of BRCA1 promoter methylation | Cell lines, PDXs | Ter Brugge et al. [47], Veeck et al. [48], Wang et al. [49] |
| -Loss of end resection regulation (53BP1, RIF1, REV7, Sheldin complex or DYNLL1 depletion) | Cell lines | Belotserkovskaya et al. [50], Xu et al. [51], Noordermeer et al. [52], Gupta et al. [53], He et al. [54] |
| -RAD51 overexpression | Ovarian cancer samples, cell lines | Kondrashova et al. [55], Liu et al. [56], Marzio et al. [57] |
| Stabilization of stalled fork (FANCD2 overexpression, RADX depletion, SMARCAL1 inactivation,) | Cell lines | Michl et al. [58], Chaudhuri et al. [59], Taglialatela et al. [60], Dungrawala et al. [61] |
NHEJ: non-homologous end-joining. PDXs: patient-derived xenografts.