Table 4 List of identified sensitivity and resistance markers to PARP inhibitors in the preclinical setting
From: Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies
Biomarker | Models | Mechanism | PARP Inhibitor | Effect | References |
|---|---|---|---|---|---|
Fusion genes | |||||
RUNX1-RUNX1T1 | mouse HSCs and primary AML | Downregulation of Rad51, ATM, BRCA1, and BRCA2 | Olaparib, veliparib | Sensitive | |
PML-RARA | mouse HSCs and primary AML | Downregulation of Rad51, ATM, BRCA1, and BRCA2 | Olaparib, veliparib | Sensitive | [131] |
KMT2A-MLLT3 | mouse HSCs | HOXA9 overexpression | Olaparib, veliparib | Sensitive in combination with chemotherapy | |
TCF3-HLF | ALL | MCPH1 downregulation and consequently HR deficiency | Olaparib | Sensitive | [134] |
Activated signaling | |||||
FLT3-ITD | murine Lin-cKit + BM cells, primary AML | PARP1 downregulation | Olaparib, talazoparib | Resistant | [135] |
FLT3-ITD | BaF3, MV4-11, murine Lin-cKit + BM cells, primary AML | FLT3i mediates the downregulation of BRCA1/2, PALB2 and RAD51 | Olaparib, talazoparib | Synthetic lethal with FLT3i | [136] |
FLT3-ITD;Tet2−/− | murine Lin-cKit + BM cells, primary AML | BRCA1 and LIG4 downregulation; inhibition of TGFβR downregulates ATM, BRCA1, BRCA2, DNA-PKcs and LIG4 | Olaparib, talazoparib | Sensitive; synthetic lethal with FLT3i + TGFβRi | |
FLT3-ITD;Tet2−/−; Dnmt3a-/- | murine Lin-cKit + BM cells, primary AML | BRCA1 and LIG4 downregulation | Olaparib, talazoparib | Sensitive | [135] |
FLT3-ITD; Dnmt3a−/− | murine Lin-cKit + BM cells, primary AML | PARP1 downregulation | Olaparib, talazoparib | Resistant | [135] |
RUNX1-RUNX1T1 and KIT mut | Kasumi-1, human Lin − CD34 + , primary AML | downregulation of BRCA1 and BRCA2 and the DNA-PK | Olaparib | Synthetic lethal with c-KITi | [138] |
JAK2V617F | SET2, HEL, PDX | activation of the ATR-Chk1 pathway | Veliparib | Synthetic lethal with busulfan | [139] |
Cohesin complex | |||||
STAG2,SMC1 and RAD21 mutations | U937, mouse HSCs and PDX | Accumulation of dsDNA breaks; stalled replication forks | Talazoparib | Sensitive | [140] |
TP53 | |||||
Trp53/Bcor mut | mouse HSCs | Not described | Talazoparib, veliparib | Sensitive | [141] |
IDH1/2 | |||||
IDH1/2 mutations | Primary AML, HCT116 | Downregulation of ATM | Olaparib, talazoparib | Sensitive | |
TET1 | |||||
TET1 expression | T-ALL | Alteration in the expression of different DNA repair and cell cycle genes | Olaparib | Sensitive | [144] |