PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword
Abstract
:Simple Summary
Abstract
1. Introduction
2. Chemical Biology of PARP Inhibitors
2.1. Structure and Function of ADP-Ribosyltransferases
2.2. Proposed Mechanisms of Synthetic Lethality in HRD
2.2.1. Inhibition of Base Excision Repair
2.2.2. PARP Trapping
2.2.3. Impaired Recruitment of BRCA1
2.2.4. Activation of NHEJ
2.2.5. Inhibition of Alt-EJ
2.2.6. Destabilization of Stalled Replication Forks
2.3. Clinical PARP Inhibitors
2.3.1. Olaparib
2.3.2. Talazoparib
2.3.3. Rucaparib
2.3.4. Niraparib
2.3.5. Veliparib
2.3.6. Pamiparib
3. PARP Inhibitors for the Treatment of Myeloid Neoplasms
3.1. Rationale for PARP Inhibition in Myeloid Neoplasms
3.2. Pre-Clinical Efficacy in Myeloid Neoplasms
Disease | Genotype(s) | Phenotype | Results of PARPi Monotherapy | Ref(s) |
---|---|---|---|---|
AML | FLT3-ITD mutant | Upregulation of RAD51 via STAT5 activation. Rapid depletion of γH2AX with highly active DSB repair. | Modest anti-leukemic activity seen with PARPi monotherapy in cell lines. Reduction in AML-initiating FLT3-ITD+ cells and clonogenic cells in bone marrow under hypoxic conditions. No significant reduction in leukemic burden or prolongation of survival in primary FLT3-ITD+ AML murine xenografts. | [158,162] |
AML | IDH1/2 mutant | Increased 2HG inhibits KDM4A/B, ALKBH, ATR, and ATM to induce HRD and DSB persistence. | Primary IDH1/2-mutant AML cells possessed a 2HG-dependent DSB repair defect that conferred sensitivity to PARPi in vitro; sensitivity was reversed with IDH1/2 inhibitors. | [149,150,151] |
AML | RUNX1- RUNX1T1 (AML1-ETO) positive | Downregulation of DNA repair genes, including BRCA2. High mutation frequency with mutator phenotype. Aberrant TET1 expression and DNA methylation. | Reduced colony-forming potential in RUNX1-RUNX1T1 transformed primary cells and patient-derived cell-lines. Prolonged survival in RUNX1-RUNX1T1 AML xenograft model. DNA damage-induced differentiation of PML-RARα transformed leukemic blasts. | [38,42,148,163] |
AML | Cohesin (STAG2) mutant | High dependency on DDR pathways. Increased replication fork stalling. | AML (including STAG2-mutant) cell lines were sensitive to PARPi both in vitro and in vivo (xenograft model). Primary STAG2-mutant AML samples exhibited dose-dependent sensitivity to PARPi. PARPi depleted cohesin-mutant clones in a Tet2/Stag2-mutant murine model of MDS/AML. | [153] |
APL | PML-RARα positive | Reduced MSH6, MLH1, BRCA1, and RAD51 expression. Repression of CHEK1, CHK2, and several BER genes induces a mutator phenotype. | Reduced colony-forming potential in PML-RARα transformed primary cells and patient-derived cell-lines. Suppressed disease onset in an ATRA-resistant APL xenograft model. DNA damage-induced differentiation of PML-RARα transformed leukemic blasts. | [38,39,152,164] |
CML | BCR-ABL positive | Reduced translation of BRCA1 mRNA. Functional BRCA1 deficiency. HR downregulation and accumulation of DSBs. | Increased DSBs and reduced clonogenic potential of imatinib-refractory CML cell lines and primary samples, including under hypoxic conditions mimicking the bone marrow microenvironment. Eliminated quiescent cells in an inducible mouse model of chronic-phase CML. Reduced leukemic burden up to 10-fold in a BCR-ABL1+ leukemia xenograft model. | [146,147,159] |
MLL | MLL-AF9 | High burden of oxidative DNA damage. Increased PARP1 expression and acetylation. | MLL-AF9 transformed murine bone marrow cells were only modestly sensitive to PARPi monotherapy. RUNX1-RUNX1T1-positive murine cells were highly sensitive to PARPi. Reduced the number of leukemic stem cells in primary human AML (MLL-AF9+) samples in vitro. PARPi and cytotoxic drugs (doxorubicin and cytarabine) exert additive anti-MLL-AF9 leukemia effects in mice. No significant reduction in leukemic burden was seen in a syngeneic mouse model of MLL-AF9+ leukemia (except when PARP inhibition was combined with cytotoxic drugs). MLL-AF9-transformed cells were resistant to olaparib monotherapy. No significant effect of olaparib on mice transplanted with wild-type MLL-AF9 leukemic cells. Hoxa9-deficient MLL-AF9 cells were highly sensitive to PARPi. | [38,165,166,167] |
MPN | JAK2 (V617F) MPL (W515L) CALR (del52) positive | Reduced formation of RAD51 foci. Modest down-regulation of BRCA1/2. Accumulation of ROS-induced DSBs. | Modest in vitro sensitivity across several MPN cell lines, though sensitivity of primary MPN samples was variable. Primary MPN cells exhibited reduced colony formation in vitro after PARPi treatment. Veliparib monotherapy did not significantly prolong survival in a murine xenograft model. | [160,168,169] |
3.3. Clinical Efficacy in Myeloid Neoplasms
3.4. Biomarkers of PARPi Sensitivity
3.5. Mechanisms of PARP Inhibitor Resistance
3.6. Challenges and Future Directions in Development of PARP Inhibitors for Myeloid Neoplasms
4. Myeloid Neoplasms Emerging with PARP Inhibitor Therapy
4.1. Recognition of PARP Inhibitor Related Myeloid Neoplasms
- Is there a subset of patients who are at a particularly high risk of developing therapy-related MDS or AML while receiving treatment with a PARPi?
- If so, how can we identify this group of high-risk patients to better stratify the risks and benefits of PARPi therapy?
- Do germline mutations in BRCA1, BRCA2, BARD1, RAD51, TP53, or PALB2—which are commonly encountered in patients with ovarian or breast cancer—confound the picture by increasing the risk of therapy-related MDS and AML?
- Is the risk of therapy-related myeloid neoplasms cumulative with continued PARPi therapy?
- What is the contribution of other DNA-damaging modalities—including conventional chemotherapy and radiation therapy—to the emergence of therapy-related myeloid neoplasms?
4.2. Epidemiology and Characteristics of PARPi-Related Myeloid Neoplasms
4.3. Reconciling the Contradictory Effects of PARP Inhibitors
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Class | Agent(s) | PARPi(s) | Mechanism(s) | Results of Combination Therapy | Ref(s) |
---|---|---|---|---|---|
Alkylating agents | Temozolomide Busulfan | Olaparib Veliparib | Temozolomide induced abasic sites and resultant SSBs. Busulfan stalled replication forks through DNA strand crosslinking. Combination with olaparib, but not veliparib, significantly increased PARP trapping. | PARPi showed synergy with temozolomide (CI < 0.3) and busulfan (CI 0.40–0.55) in vitro. With temozolomide, olaparib was >100-fold more potent than veliparib due to enhanced PARP trapping with olaparib. Busulfan plus veliparib was associated with activation of the ATR-Chk1 pathway and G2/M arrest in MPN cell lines, and modestly prolonged survival in a murine xenograft model of MPN-AML. | [169,170] |
Conventional chemotherapy | Doxorubicin Daunorubicin Cytarabine 5-Fluorouracil | Olaparib Talazoparib Rucaparib | Increased abundance and phosphorylation of H2AX and CHK1. Accumulation of oxidative DNA damage. Suppression of ATM. | Increased PARPi sensitivity in vitro with accumulation of DNA damage, replication arrest, and apoptosis. Synergistic cytotoxicity against primary IDH1/2-mutant AML cells associated with ATM suppression. Rucaparib cooperates with 5-FU to accumulate DSBs in vitro and significantly enhance cytotoxicity in a syngeneic murine model of AML. Olaparib potentiates anti-leukemogenic activity of conventional chemotherapy in MLL. | [150,165,166,171] |
Topoisomerase poisons | Camptothecin Etoposide | Olaparib Veliparib | Camptothecin-induced DNA lesions induce replication fork stalling, which depend in part on PARP1 for restart. | PARPi treatment was synergistic with camptothecin (CI < 0.3) in vitro; no increase in PARP/DNA complexes was detected using an insensitive assay, but genetic studies suggest a key role for PARP trapping. No synergy was seen with PARPi plus etoposide. | [104,170,172] |
DNMT inhibitors | Decitabine Azacitidine | Olaparib Talazoparib | Downregulation of RAD51, BRCA1/2, FEN1, and FANCD2 leads to HRD. Trapped both DNMT and PARP1 at sites of DNA damage. Repair of decitabine-induced DNA lesions is mediated by BER and requires XRCC1, recruitment of which is impaired by PARPi. | Decitabine plus olaparib was synthetically lethal in a large panel of AML cell lines, with synergy driven by PARPi-mediated inhibition of XRCC1 recruitment. DNMTi treatment induced HRD in most primary AML samples, and combination therapy (decitabine + talazoparib) significantly reduced subsequent colony formation. Combination therapy reduced leukemic burden and prolonged survival in murine AML xenografts. Synergistic antiproliferative effects against ATO-sensitive and ATO-resistant APL cell lines, with PARPi and demethylating agents (azacitidine, decitabine, and ascorbate). Synergistic cytotoxic and differentiating effects on primary MDS cells grown on culture. | [143,156,157,164,173,174] |
HDAC inhibitors | Entinostat Trichostatin A Apcidin | PJ34 EB47 KU-0058948 Talazoparib | Induced DNA damage, phosphorylation of H2AX and ATM, and ultimately apoptosis. Promoted PARP trapping and impaired NHEJ via differential acetylation of Ku70/80. | HDAC inhibition enhanced PARP trapping, and co-treatment with a PARPi significantly increased apoptosis in AML cell lines. Synergistic cytotoxicity was seen with MS275 + PARPi combination therapy in select AML cell lines. | [143,175,176] |
JAK2 inhibitors | Ruxolitinib | Olaparib Talazoparib | Impaired BRCA-mediated HR and DNA-PK-mediated NHEJ, thereby increasing sensitivity to PARP inhibition. | Ruxolitinib enhanced PARPi sensitivity in both MPN cell lines and primary samples with synergistic cytotoxicity in vitro. The combination of ruxolitinib, hydroxyurea, and talazoparib provided significantly greater cytoreduction than mono-/doublet therapy in both a murine MPN model and primary MPN xenograft model. | [160] |
BCR-ABL inhibitors | Imatinib | Talazoparib | Downregulation of RAD51 and LIG4 to impair HR and NHEJ, respectively | Induction of DSBs and reduced clonogenic potential of imatinib-refractory CML cell lines and primary samples. Reduction in LSC-enriched quiescent cells in an inducible mouse model of chronic-phase CML. Extended disease latency in both primary and secondary recipient mice in a primary xenograft model. Synergistic 40-fold reduction in disease burden in a BCR-ABL1+ leukemia xenograft model. | [146,159] |
FLT3-ITD inhibitors | Quizartinib | Olaparib Talazoparib Veliparib | Downregulation of BRCA1/2, PALB2, RAD51, and LIG4 impairs HR and NHEJ to induce HRD. Combination therapy caused accumulation of lethal DSBs. PARPi destabilize STAT5 to reduce aberrant FLT3-ITD signaling | Combination therapy exhibited synergistic activity against proliferating and quiescent leukemic stem/progenitor cells, eliminating both from primary AML samples. Combination therapy reduced leukemic burden in primary AML xenograft mice and prolonged survival in secondary recipients. PARPi and TKI combination therapy exhibited synergistic cytotoxicity in both TKI-sensitive and TKI-resistant AML cell lines. | [158,177] |
WEE1 inhibitors | AZD1775 | Olaparib | Inhibition of WEE1 impairs HR by indirectly inhibiting BRCA2. Combination therapy resulted in elevated γH2AX, accumulation of DNA damage, and induction of apoptosis. | Mild synergy between WEE1 and PARP inhibition was seen in cell lines harboring FLT3-ITD, while FLT3 wild-type cells were relatively insensitive, independent of TP53 status. Significantly prolonged survival in a murine model of FLT3-ITD+ AML and reduced colony formation in primary AML samples. | [178] |
TRAIL | rTRAIL | Olaparib Veliparib | PARPi upregulate TNFRSF6 and TNFRSF10B expression via potentiation of the Sp1 transcription factor and NF-kB, increasing sensitivity to TRAIL. | Both olaparib and veliparib enhanced the sensitivity of myeloid cell lines to TRAIL in vitro. Though olaparib had no consistent activity alone, it sensitized most primary AML isolates to TRAIL and reduced colony formation. | [161,179] |
Antibody drug conjugates | Gemtuzumab ozogamicin | Olaparib | Calicheamicin induces both SSBs and DSBs, invoking PARP activation. | The IC50 value for GO was reduced from 24 to 13 ng/mL when combined with olaparib; the CI was 0.86, indicating synergistic cytotoxicity. | [144] |
Trial | Year | Intervention(s) | Phase | Disease(s) a | N | CRR | ORR | OS b | Ref |
---|---|---|---|---|---|---|---|---|---|
NCT01399840 | 2014 | Talazoparib | I | AML/MDS CLL/MCL | 25 8 | 0% 0% | 0% 0% | N/A | [180] |
NCT01139970 | 2017 | Veliparib + Temozolomide | I | AML | 48 | 17% | 33% | 5.3 | [181] |
NCT00588991 | 2017 | Veliparib + Topotecan ± Carboplatin | I | AML, MPN, CMML | 99 | 14% | 33% | 15.3 c | [182] |
ISRCTN34386131 | 2017 | Olaparib | I | CLL, MCL, T-PLL | 15 | 0% | 0% | 4.3 | [183] |
Trial | Phase | Intervention(s) | Population(s) a | Status |
---|---|---|---|---|
NCT03289910 | II | Topotecan + Carboplatin ± Veliparib | AML, MDS, MPN, CMML | Active (not recruiting) |
NCT02878785 | I/II | Talazoparib + Decitabine | AML (phase I) AML, untreated (phase II) | Active (not recruiting) |
NCT03953898 | II | Olaparib | IDH1/2-mutant AML/MDS | Recruiting |
NCT03974217 | I | Talazoparib | Cohesin-mutant AML/MDS | Recruiting |
Authors | N | PARPi | Myeloid Neoplasm | SOT | Karyotype | NGS | SOT Status at Diagnosis | Median OS |
---|---|---|---|---|---|---|---|---|
Martin et al. [238] | 20 | Olaparib (94%) Rucaparib (6%) | AML (45%) MDS (55%) | Ovarian | 95% complex | DDR pathway mutations in 83% | 55% in CR | 4.3 months |
Kwan et al. [239] | 22 | Rucaparib | AML 41% MDS 59% * | Ovarian | 53% complex; 80% with chrom. 5 or 7 alteration | NR | NR | NR |
Morice et al. [19] | 178 | Olaparib (75%) Niraparib (18%) Rucaparib (6%) Talazoparib (1%) Veliparib (1%) | AML (44%) MDS (56%) | Ovarian (85%) Prostate (7%) Breast (5%) Pancreatic (2%) | NR | NR | Response (85%) Progression (15%) | NR (45% had died on follow-up) |
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Csizmar, C.M.; Saliba, A.N.; Swisher, E.M.; Kaufmann, S.H. PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword. Cancers 2021, 13, 6385. https://doi.org/10.3390/cancers13246385
Csizmar CM, Saliba AN, Swisher EM, Kaufmann SH. PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword. Cancers. 2021; 13(24):6385. https://doi.org/10.3390/cancers13246385
Chicago/Turabian StyleCsizmar, Clifford M., Antoine N. Saliba, Elizabeth M. Swisher, and Scott H. Kaufmann. 2021. "PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword" Cancers 13, no. 24: 6385. https://doi.org/10.3390/cancers13246385
APA StyleCsizmar, C. M., Saliba, A. N., Swisher, E. M., & Kaufmann, S. H. (2021). PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword. Cancers, 13(24), 6385. https://doi.org/10.3390/cancers13246385