Preclinical studies of PARP inhibitors in DDR-defective hematologic malignancies
| Malignancy . | Study . | PARP inhibitor . | Drug combination . | Preclinical models . | Findings . |
|---|---|---|---|---|---|
| AML | Molenaar et al, 2018101 | Olaparib, talazoparib | Daunorubicin | Primary tumor cells | IDH1/2 mutation sensitizes AML cells to daunorubicin and PARP inhibition. Combined treatment with PARP inhibitor and daunorubicin has additive effect. |
| AML | Esposito et al, 2015105 | Olaparib, veliparib | GSK3 inhibitor | Cell lines, AML cell line–derived xenograft model | AML cells driven by AML1-ETO and PML-RARA are hypersensitive to PARP inhibition. Combined PARP/GSK3 inhibition can overcome PARP inhibitor resistance in MLL-driven leukemia. |
| AML, MDS | Tothova et al, 2021106 | Talazoparib | — | Cell lines, transgenic murine model | Cohesin-mutant AML/MDS displays enhanced sensitivity to PARP inhibition in vitro and in vivo |
| AML | Maifrede et al, 2018107 | Talazoparib, olaparib | FLT3 inhibitors: AC220, gilteritinib, and crenolanib | Cell lines, primary tumor cells, transgenic murine model, and PDX models | FLT3 inhibition suppresses DNA DSB repair and sensitizes FLT3-ITD–positive leukemia to PARP inhibition. FLT3 and PARP inhibition delays AML onset in a FLT3-ITD–positive murine model. |
| CML | Tobin et al, 2013104 | NU1025 | DNA ligase inhibitor | Cell lines and primary tumor cells | Imatinib-resistant CML cells are sensitive to combined DNA ligase and PARP inhibition. In patients with CML, this sensitivity correlates with the expression in CML cells of PARP1 and DNA ligase IIIα, and with alternative NHEJ activity. |
| Myeloid malignancies | Poh et al, 2019108 | Veliparib | — | Cell lines and primary tumor cells | Myeloid neoplasms exhibit homologous recombination defects caused by the epigenetic silencing of BRCA1. BRCA1-repressed leukemic cells show increased miR-155 expression and sensitivity to PARP inhibition. |
| T-ALL | Bamezai et al, 2021109 | Olaparib | — | Cell lines, primary tumor cells, and T-ALL cell line–derived xenograft model | TET1 is highly expressed in T-ALL cells, interacts with PARP, and regulates cell cycle and DNA repair genes. PARP inhibitor abrogates TET1 expression and antagonizes the growth of T-ALL cells. |
| CLL, MCL | Weston et al, 2010110 | Olaparib | Bendamustine, fludarabine, and cyclophosphamide | Cell lines, primary tumor cells, and MCL cell line–derived xenograft model | ATM-deficient CLL and MCL are sensitive to PARP inhibition in vitro and in vivo. PARP inhibitor sensitizes ATM-mutant CLL/MCL to chemotherapy. |
| CLL | Quijada-Alamo et al, 2020111 | Olaparib | BCR inhibitors including ibrutinib | Cell lines and primary tumor cells | Del(11q)/ATM-KO in CLL cells results in increased sensitivity to PARP inhibition. PARP inhibitor olaparib synergizes with BCR inhibition in del(11q) CLL cells. |
| CLL | Zimmermann et al, 201836 | Olaparib, talazoparib | — | Primary tumor cells | RNASEH2B-deficient CLL cells display enhanced sensitive to PARP inhibitors, especially to talazoparib, with the degree of sensitivity correlating with the number of RNASEH2B alleles lost |
| Malignancy . | Study . | PARP inhibitor . | Drug combination . | Preclinical models . | Findings . |
|---|---|---|---|---|---|
| AML | Molenaar et al, 2018101 | Olaparib, talazoparib | Daunorubicin | Primary tumor cells | IDH1/2 mutation sensitizes AML cells to daunorubicin and PARP inhibition. Combined treatment with PARP inhibitor and daunorubicin has additive effect. |
| AML | Esposito et al, 2015105 | Olaparib, veliparib | GSK3 inhibitor | Cell lines, AML cell line–derived xenograft model | AML cells driven by AML1-ETO and PML-RARA are hypersensitive to PARP inhibition. Combined PARP/GSK3 inhibition can overcome PARP inhibitor resistance in MLL-driven leukemia. |
| AML, MDS | Tothova et al, 2021106 | Talazoparib | — | Cell lines, transgenic murine model | Cohesin-mutant AML/MDS displays enhanced sensitivity to PARP inhibition in vitro and in vivo |
| AML | Maifrede et al, 2018107 | Talazoparib, olaparib | FLT3 inhibitors: AC220, gilteritinib, and crenolanib | Cell lines, primary tumor cells, transgenic murine model, and PDX models | FLT3 inhibition suppresses DNA DSB repair and sensitizes FLT3-ITD–positive leukemia to PARP inhibition. FLT3 and PARP inhibition delays AML onset in a FLT3-ITD–positive murine model. |
| CML | Tobin et al, 2013104 | NU1025 | DNA ligase inhibitor | Cell lines and primary tumor cells | Imatinib-resistant CML cells are sensitive to combined DNA ligase and PARP inhibition. In patients with CML, this sensitivity correlates with the expression in CML cells of PARP1 and DNA ligase IIIα, and with alternative NHEJ activity. |
| Myeloid malignancies | Poh et al, 2019108 | Veliparib | — | Cell lines and primary tumor cells | Myeloid neoplasms exhibit homologous recombination defects caused by the epigenetic silencing of BRCA1. BRCA1-repressed leukemic cells show increased miR-155 expression and sensitivity to PARP inhibition. |
| T-ALL | Bamezai et al, 2021109 | Olaparib | — | Cell lines, primary tumor cells, and T-ALL cell line–derived xenograft model | TET1 is highly expressed in T-ALL cells, interacts with PARP, and regulates cell cycle and DNA repair genes. PARP inhibitor abrogates TET1 expression and antagonizes the growth of T-ALL cells. |
| CLL, MCL | Weston et al, 2010110 | Olaparib | Bendamustine, fludarabine, and cyclophosphamide | Cell lines, primary tumor cells, and MCL cell line–derived xenograft model | ATM-deficient CLL and MCL are sensitive to PARP inhibition in vitro and in vivo. PARP inhibitor sensitizes ATM-mutant CLL/MCL to chemotherapy. |
| CLL | Quijada-Alamo et al, 2020111 | Olaparib | BCR inhibitors including ibrutinib | Cell lines and primary tumor cells | Del(11q)/ATM-KO in CLL cells results in increased sensitivity to PARP inhibition. PARP inhibitor olaparib synergizes with BCR inhibition in del(11q) CLL cells. |
| CLL | Zimmermann et al, 201836 | Olaparib, talazoparib | — | Primary tumor cells | RNASEH2B-deficient CLL cells display enhanced sensitive to PARP inhibitors, especially to talazoparib, with the degree of sensitivity correlating with the number of RNASEH2B alleles lost |
ALL, acute lymphoblastic leukemia; BCR, B-cell receptor signaling; KO, knockout; MCL, mantle cell lymphoma; MLL, mixed lineage leukemia; miR, microRNA; PDX, patient–derived xenograft; T-ALL, T-cell acute lymphoblastic leukemia.