From: The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment
Histological type | PARPi resistance | Cell line | Mutations | Cell cycle checkpoint inhibitors + PARPi | Synergism | Effect of combo on ATR/ CHK1 | Effect of combo on DSBs | Effect of combo on HR | Effect of combo on replication forks | Cell cycle alterations | Effect of combo on apoptosis | References |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Ovary | Acquired PR | PEO1-PR | BRCA2-MUT | ATRi + PARPi (AZD6738 + Olaparib) | Yes | ↑ | ↑ | ↓ | ↓ | No | ↑ | [125] |
JHOS4-PR | BRCA1-MUT | ATRi + PARPi (AZD6738 + Olaparib) | Yes | ↑ | ↑ | No | ↓ | No | ↑ | [125] | ||
UWB1.289 SYR1 | BRCA1-MUT | ATRi + PARPi (VE-821 + Olaparib) | Ye | – | – | ↓ | ↓ | – | [124] | |||
UWB1.289 SYR12* | BRCA1-MUT | CHK1i + PARPi (Prexasertib + Olaparib) | Yes | – | – | – | – | [86] | ||||
UWB1.289 SYR13 | BRCA1-MUT | ATRi + PARPi (VE-821 + Olaparib) | Yes | – | – | ↓ | – | – | [124] | |||
UWB1.289 SYR1 | BRCA1-MUT | CHK1i + PARPi (Prexasertib + Olaparib) | Yes | – | – | – | – | – | – | [86] | ||
BR5-R1 | BRCA1-MU | ATRi + PARPi (VE-821 + Olaparib) | Yes | – | – | – | – | [124] | ||||
De novo PR | UWB1.289/BRCA1 ± | BRCA1 ± | ATRi + PARPi (VE-821 + Olaparib) | No | – | – | ↓ | No | – | – | [124] | |
ATRi + PARPi (AZD6738 + Olaparib) | Yes | ↑ | ↑ | ↓ | – | No | – | [125] | ||||
UWB1.289/53BP1−/− | BRCA1-MUT | ATRi + PARPi (AZD6738 + Olaparib) | Ye | – | – | – | – | No | – | [125] | ||
COV362/53BP1−/− | BRCA1-MUT | CHK1i + PARPi (Prexasertib + Olaparib) | Yes | – | – | ↓ | – | – | – | [86] | ||
Kuramochi | BRCA2-nonse mutation (c.6952C > T) | ATRi + PARPi (AZD6738 + Olaparib) | Yes | ↑ | ↑ | No | – | No | – | [125] | ||
PEO4 | BRCA2-reversion mutation | ATRi + PARPi (AZD6738 + Olaparib) | Yes | ↓ | – | – | – | G2/M↑ | ↑ | [141] | ||
CHK1i + PARPi (Prexasertib + Olaparib) | Yes | pATR↑/pCHK1↓ | ↑ | ↓ | – | G2/M↓ | ↑ | [143] | ||||
Preexisting PR | OV-9 | TP53-MUT BRCA-WT | CHK1i + PARPi (Prexasertib + Olaparib) | Yes | pATR↑/pCHK1↓ | ↑ | ↓ | – | – | ↑ | [143] | |
ATRi + PARPi (AZD6738 + Olaparib | Yes | ↑ | ↑ | – | – | – | ↑ | [123] | ||||
CHK1i + PARPi (MK8776 + Olaparib) | Yes | ↑ | ↑ | – | – | – | [123] | |||||
SKOV3 | BRCA-WT | ATRi + PARPi + siBRCA1 (VE-821 + Velaparib + siBRCA1) | Yes | – | – | ↓ | – | – | – | [158] | ||
ATRi + PARPi (AZD6738 + Olaparib) | Yes | – | ↑ | – | – | – | ↑ | [123] | ||||
CHK1i + PARPi (MK8776 + Olaparib) | Yes | – | ↑ | – | – | – | ↑ | [123] | ||||
TOV112D | BRCA1-WT | CHK1i + PARPi (Prexasertib + Olaparib) | Yes | – | – | – | – | – | – | [86] | ||
ES2 | BRCA1-WT | CHK1i + PARPi (Prexasertib + Olaparib) | Yes | – | – | – | – | – | – | [86] | ||
OVCAR-8 | BRCA-WT | ATRi + PARPi + siBRCA1 (VE-821 + Velaparib + siBRCA1) | Yes | – | – | – | – | – | [158] | |||
OVCAR3 | BRCA wild type; TP53-MUT(R248Q) | CHK1i + PARPi (Prexasertib + Olaparib) | Yes | pATR↑/Pchk1↓ | ↑ | ↓ | – | G2/M↓ | ↑ | [143] | ||
WEE1i + PARPi (AZD1775 + Olaparib) | Yes | – | – | – | – | M↑ | ↑ | [159] | ||||
PARPi-sensitive | PEO1 | BRCA2-MUT(c.C4965G) | ATRi + PARPi (AZD6738 + Olaparib) | Yes | ↓ | ↑ | – | – | G2/M↓ | ↑ | [141] | |
ATRi + PARPi (VE-821 + Velaparib) | Yes | – | – | – | – | – | – | [158] | ||||
CHK1i + PARPi (MK8776 + Olaparib | Yes | ↓ | ↑ | – | – | G2/M↓ | ↑ | [141] [123] | ||||
CHK1i + PARPi (Prexasertib + Olaparib) | Yes | pATR↑/Pchk1↓ | ↑ | ↓ | – | G2/M↓ | ↑ | [143] | ||||
– | EM9 | XRCC1−/− | ATRi + PARPi (NU6027 + Rucaparib) | Yes | – | – | – | – | – | – | [160] | |
Breast | Preexisting PR | HCC1937 | BRCA1-deficient | ATRi + PARPi (VE-821 + Velaparib) | Yes | – | – | ↓ | – | – | – | [124] |
– | MCF7 | – | ATRi + PARPi (NU6027 + Rucaparib) | Yes | – | ↑ | ↓ | – | – | – | [160] | |
Pancreas | Acquired PR | R-AKC | ATM-MUT | ATRi + PARPi + DNA-PKi + P-gpi (VE-822 + Olaparib + CC-115 + Elacridar) | Yes | – | – | – | – | G2/M↑ | – | [132] |
Lung | De novo PR | VC8-B2 | BRCA2 + / + | ATRi + PARPi (NU6027 + Rucaparib) | Yes | – | – | ↓ | – | – | – | [160] |
CHK1i + PARPi (PF-47736 + Rucaparib) | Yes | ↓ | ↑ | ↓ | – | S↓G2/M↓ sub-G1↑ | – | [144] | ||||
Endometrium | Preexisting PR | Hec50 | BRCA-WT;TP53-MUT(intron 6) | BRCA-WT;TP53-MUT(intron 6) | Yes | – | – | – | – | M↑ | ↑ | [159] |
Gastric | – | MKN45 | – | WEE1i + PARPi (AZD1775 + Olaparib) | Yes | – | ↑ | ↓ | – | G2/M↓ | ↑ | [146] |
– | AGS | – | WEE1i + PARPi (AZD1775 + Olaparib) | Yes | – | ↑ | ↓ | – | G2/M↓ | ↑ | [146] | |
Brain | – | MGG18 | Non MYC-MUT | ATRi + PARPi (VE-822 + Olaparib) | Yes | ↑ | ↑ | ↓ | – | – | ↑ | [161] |