Preclinical data on the development of PARPi
| Reference . | Genetics/studied parameters . | Disease . | Sensitivity to PARPi/results . |
|---|---|---|---|
| Esposito et al, 2015 | Synthetic lethality of oncogenic transcription for leukemia treatment | AML | Sensitivity to PARPis of AML cells with low expression of members of the DDR pathway. AML cells driven by repressive transcription factors, including AML1-ETO and PML-RARα fusion oncoproteins, are sensitive to PARPis. Sensitivity to PARPis of AML cells with low expression of Rad51, ATM, BRCA1, and BRCA2. Genetic or pharmacological inhibition of HOXA9 impairs DDR and sensitizes MML leukemia to PARPis. |
| Zampieri et al, 2009 | DNA methylation | Ovarian cancer, breast cancer | PARPis with HMAs lead to synergistic inhibition. Inactivation and trapping of DNMT to DNA facilitates the role of BER machinery. |
| Lord et al, 2017 | Synthetic lethality, DNA repair | Ovarian cancer, breast cancer | PARPis trap PARP1 on DNA, preventing autoPARylation and PARP1 release from the site of damage of BRCA-mutant cells. |
| Boussios et al, 2012 | Synthetic lethality, DNA repair | Ovarian cancer, breast cancer | Tumors carrying mutations in BRCA1/2 implicated in homologous repair deficiency are particularly sensitive to PARPis. |
| Meng et al, 2014 | Apoptosis, knockdown of PARP1 and/or PARP2 | AML | Synergistic action of PARPi with death ligands results in enhanced expression of DR5 and Fas and sensitivity to treatment with multiple death ligands (agonistic anti-Fas antibody, recombinant human TRAIL, and agonistic anti-DR5 antibody). |
| Faraoni et al, 2018 | Apoptosis resistance, modulation of FAS and TRAIL receptors | AML | AML ΒΜ samples express FAS and DR5 transcripts at lower levels than normal BM. Apoptosis triggered by olaparib is associated with a dose-dependent up-regulation |
| Maifrede et al, 2017 | PARP1 knockdown | AML bearing MLL translocations | inhibitors of PARP1 enhance the therapeutic effect of cytotoxic drugs against MLL leukemias. |
| Molenaar et al, 2018 | Correlation of IDH1/IDH2 mutations to DNA damage and responses to PARPis | AML | IDH1/2MUT cells are sensitive to PARPi as monotherapy or/and in combination with DNA-damaging agents. Concomitant administration of IDH1/2MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2MUT AML. |
| Faraoni et al, 2014 | Αpoptosis, in vitro sensitivity to olaparib | AML | Olaparib induced cell death in the majority of AML samples (88%) and tested cell lines. Olaparib preferentially killed leukemic blasts and did not affect the viability of normal BM and CD34− peripheral blood cells. |
| Nieborowska-Skorska et al, 2017 | DNA repair | MPN | PARPi combination with ruxolitinib-mediated inhibition of DSB repair and/or hydroxyurea causes accumulation of lethal DSBs, resulting in elimination of MPN cells. |
| Patel et al, 2019 | DNA repair, genomic instability | MPN | In veliparib and busulfan treated SET2 and HEL cells, veliparib decreased busulfan’s IC50. Combination treatment of SET2 cells caused G2M arrest in 53% of cells, compared with 30% with veliparib alone and 35% with busulfan alone. |
| Muvarak et al, 2016 | DNA damage-related binding between DNMTs and PARP1 | AML, breast cancer | Combining DNMTi and PARPi (talazoparib) increases tight binding of PARP1 in chromatin, frequency of DSBs, and synergistic cytotoxicity while it decreases clonogenicity |
| Zhao et al, 2017 | Synthetic lethality | AML driven by MLL fusion proteins | Combining olaparib with DNMT inhibitor induce cell-cycle block and apoptosis. Olaparib can sensitize MLL leukemic cells to both DNMT inhibitors and chemotherapy agents. |
| Reference . | Genetics/studied parameters . | Disease . | Sensitivity to PARPi/results . |
|---|---|---|---|
| Esposito et al, 2015 | Synthetic lethality of oncogenic transcription for leukemia treatment | AML | Sensitivity to PARPis of AML cells with low expression of members of the DDR pathway. AML cells driven by repressive transcription factors, including AML1-ETO and PML-RARα fusion oncoproteins, are sensitive to PARPis. Sensitivity to PARPis of AML cells with low expression of Rad51, ATM, BRCA1, and BRCA2. Genetic or pharmacological inhibition of HOXA9 impairs DDR and sensitizes MML leukemia to PARPis. |
| Zampieri et al, 2009 | DNA methylation | Ovarian cancer, breast cancer | PARPis with HMAs lead to synergistic inhibition. Inactivation and trapping of DNMT to DNA facilitates the role of BER machinery. |
| Lord et al, 2017 | Synthetic lethality, DNA repair | Ovarian cancer, breast cancer | PARPis trap PARP1 on DNA, preventing autoPARylation and PARP1 release from the site of damage of BRCA-mutant cells. |
| Boussios et al, 2012 | Synthetic lethality, DNA repair | Ovarian cancer, breast cancer | Tumors carrying mutations in BRCA1/2 implicated in homologous repair deficiency are particularly sensitive to PARPis. |
| Meng et al, 2014 | Apoptosis, knockdown of PARP1 and/or PARP2 | AML | Synergistic action of PARPi with death ligands results in enhanced expression of DR5 and Fas and sensitivity to treatment with multiple death ligands (agonistic anti-Fas antibody, recombinant human TRAIL, and agonistic anti-DR5 antibody). |
| Faraoni et al, 2018 | Apoptosis resistance, modulation of FAS and TRAIL receptors | AML | AML ΒΜ samples express FAS and DR5 transcripts at lower levels than normal BM. Apoptosis triggered by olaparib is associated with a dose-dependent up-regulation |
| Maifrede et al, 2017 | PARP1 knockdown | AML bearing MLL translocations | inhibitors of PARP1 enhance the therapeutic effect of cytotoxic drugs against MLL leukemias. |
| Molenaar et al, 2018 | Correlation of IDH1/IDH2 mutations to DNA damage and responses to PARPis | AML | IDH1/2MUT cells are sensitive to PARPi as monotherapy or/and in combination with DNA-damaging agents. Concomitant administration of IDH1/2MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2MUT AML. |
| Faraoni et al, 2014 | Αpoptosis, in vitro sensitivity to olaparib | AML | Olaparib induced cell death in the majority of AML samples (88%) and tested cell lines. Olaparib preferentially killed leukemic blasts and did not affect the viability of normal BM and CD34− peripheral blood cells. |
| Nieborowska-Skorska et al, 2017 | DNA repair | MPN | PARPi combination with ruxolitinib-mediated inhibition of DSB repair and/or hydroxyurea causes accumulation of lethal DSBs, resulting in elimination of MPN cells. |
| Patel et al, 2019 | DNA repair, genomic instability | MPN | In veliparib and busulfan treated SET2 and HEL cells, veliparib decreased busulfan’s IC50. Combination treatment of SET2 cells caused G2M arrest in 53% of cells, compared with 30% with veliparib alone and 35% with busulfan alone. |
| Muvarak et al, 2016 | DNA damage-related binding between DNMTs and PARP1 | AML, breast cancer | Combining DNMTi and PARPi (talazoparib) increases tight binding of PARP1 in chromatin, frequency of DSBs, and synergistic cytotoxicity while it decreases clonogenicity |
| Zhao et al, 2017 | Synthetic lethality | AML driven by MLL fusion proteins | Combining olaparib with DNMT inhibitor induce cell-cycle block and apoptosis. Olaparib can sensitize MLL leukemic cells to both DNMT inhibitors and chemotherapy agents. |
AML-ETO, acute myeloid leukemia-eight twenty-one oncoprotein; ATM, ataxia-telangiectasia mutated; BER, base excision repair; BM, bone marrow; DR5, death receptor 5; FAS, FS-7-associated surface antigen; HEL, hevein-like preprotein; IC50, half-maximal inhibitory concentration; MML, myelomastocytic leukemia; PML-RARα, promyelocytic leukemia/retinoic acid receptor α; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; SET2, nucleosomal histone H3-selective methyltransferase.