PARP1 as a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) is a key mediator of various forms of DNA damage repair and plays an important role in the progression of several cancer types. The enzyme is activated by binding to DNA single-strand and double-strand breaks. Its contribution to chromatin remodeling makes PARP1 crucial for gene expression regulation. Inhibition of its activity with small molecules leads to the synthetic lethal effect by impeding DNA repair in the treatment of cancer cells. At first, PARP1 inhibitors (PARPis) were developed to target breast cancer mutated cancer cells. Currently, PARPis are being studied to be used in a broader variety of patients either as single agents or in combination with chemotherapy, antiangiogenic agents, ionizing radiation, and immune checkpoint inhibitors. Ongoing clinical trials on olaparib, rucaparib, niraparib, veliparib, and the recent talazoparib show the advantage of these agents in overcoming PARPi resistance and underline their efficacy in targeted treatment of several hematologic malignancies. In this review, focusing on the crucial role of PARP1 in physiological and pathological effects in myelodysplastic syndrome and acute myeloid leukemia, we give an outline of the enzyme's mechanisms of action and its role in the pathophysiology and prognosis of myelodysplastic syndrome/acute myeloid leukemia and we analyze the available data on the use of PARPis, highlighting their promising advances in clinical application.

Figure 1.

Role of PARP1 in DNA damage repair. PARP1 consists of a DNA-binding domain with 3 zinc finger motifs, an automodification domain that contains the BRCA1 C terminus (BRCT) domain, and a carboxy-terminal catalytic domain, which contains the active site of the enzyme. PARP1 is usually activated by DNA damage occurring as a result of the DNA damage response. The net result of its activation is the production of PAR chains, with the use of nicotinamide adenine dinucleotide (NAD⁺) as substrate. PARylation results in the recruitment of several proteins with multiple roles on DNA damage repair.

Figure 2.

Effects of PARP inhibition. PARPis are able to create their own interaction network with proteins outside the nucleus, beside the sole blockage of PARP (on target action of PARPis). By inducing signaling pathways and impacting secondary proteins, they can affect cell functions and cause metabolic responses that constitute the off-target actions of PARPi.