PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword

Abstract

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.

DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities

“…Pneumonitis and therapy-related myeloid neoplasias (t-MN), such as AML and myelodysplastic syndromes (MDS), have been reported with PARPi, but despite their rare frequency, they are potentially life-threatening, often fatal, and deserve particular attention due to their severity [ 291 ]. The t-MN is typically a late complication of some chemo- and radiotherapy, and the subtype and latency period are usually treatment-dependent [ 295 ].…”

DNA Methylation Malleability and Dysregulation in Cancer Progression: Understanding the Role of PARP1

“…In cancer, this tight regulation is disrupted by the increase or decrease in enzymatic activities and expression of these genes. In AML and breast cancer cells, DNA demethylating agents (DNMT inhibitors) improve the lethal action of PARP1 inhibitors [240][241][242][243]. Both inhibitors' synergistic impact enhances DNA damage and, as a result, tumor cytotoxicity [244,245].…”

Myeloid neoplasms on poly (ADP-ribose) polymerase inhibitor therapy

“…Given the capacity of PARPi to prolong survival in many solid organ tumors, they are here to stay. [1] Furthermore, prolonged survival on these drugs may lead to a survivorship bias resulting in a higher incidence of myeloid neoplasms stemming from prior chemotherapy. In this regard, long-term follow-up data of trials using PARPi in frontline settings without prior alkylator/ topoisomerase inhibitor exposure (e.g., carcinoma prostate) may shed some light.…”

“…Poly (ADP-ribose) polymerase inhibitors (PARPis), while predominantly being used in patients with solid malignancies with impaired homologous recombination repair, have an upcoming role in patients of acute myeloid leukemia (AML) with runt-related transcription factor 1 (RUNX1)-RUNX1 partner transcriptional co-repressor 1 (RUNX1T1)/ promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARα) fusions or fms like tyrosine kinase 3 (FLT3)/isocitrate dehydrogenase 1 (IDH1) mutations. [1] However, reports of therapy-related AML on PARPi therapy are a parallel emerging concern. is review details the current evidence about the possible mechanism, clinical features, outcomes, and possible prevention of myeloid neoplasms associated with PARPi therapy.…”