| Autor: |
Csizmar CM; Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA., Saliba AN; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.; Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA., Swisher EM; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, USA., Kaufmann SH; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA. |
| Jazyk: |
angličtina |
| Zdroj: |
Cancers [Cancers (Basel)] 2021 Dec 20; Vol. 13 (24). Date of Electronic Publication: 2021 Dec 20. |
| DOI: |
10.3390/cancers13246385 |
| Abstrakt: |
Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in BRCA -mutant disease, set the stage for cell killing. PARPi appear to be especially effective in AML with certain gene rearrangements and molecular characteristics ( RUNX1-RUNX1T1 and PML-RARA fusions, FLT3- and IDH1 -mutated). In addition, PARPi can enhance the efficacy of other agents, particularly alkylating agents, TOP1 poisons, and hypomethylating agents, that induce lesions ordinarily repaired via PARP1-dependent mechanisms. Conversely, emerging reports suggest that long-term treatment with PARPi for solid tumors is associated with an increased incidence of myelodysplastic syndrome (MDS) and AML. Here, we (i) review the pre-clinical and clinical data on the role of PARPi, specifically olaparib, talazoparib, and veliparib, in aggressive myeloid neoplasms and (ii) discuss the reported risk of MDS/AML with PARPi, especially as the indications for PARPi use expand to include patients with potentially curable cancer. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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