Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

Abstract

The members of the Poly(ADP‐ribose) polymerase (PARP) superfamily are involved in several biological processes and, in particular, in the DNA damage response (DDR). The most studied members, PARP1, PARP2 and PARP3, act as sensors of DNA damages, in order to activate different intracellular repair pathways, including single-strand repair, homologous recombination, conventional and alternative non-homologous end joining. This review recapitulates the functional role of PARPs in the DDR pathways, also in relationship with the cell cycle phases, which drives our knowledge of the mechanisms of action of PARP inhibitors (PARPi), encompassing inhibition of single-strand breaks and base excision repair, PARP trapping and sensitization to antileukemia immune responses. Several studies have demonstrated a preclinical activity of the current available PARPi, olaparib, rucaparib, niraparib, veliparib and talazoparib, as single agent and/or in combination with cytotoxic, hypomethylating or targeted drugs in acute leukemia, thus encouraging the development of clinical trials. We here summarize the most recent preclinical and clinical findings and discuss the synthetic lethal interactions of PARPi in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Despite the low frequency of genomic alterations of PARP and other DDR-related genes in acute leukemia, selective vulnerabilities have been reported in several disease subgroups, along with a “BRCAness phenotype.” AML carrying the RUNX1-RUNX1T1 or PML-RARA fusion genes or mutations in signaling genes (FLT3-ITD in combination with TET2 or TET2 and DNMT3A deficiency), cohesin complex members (STAG2), TP53 and BCOR as co-occurring lesions, IDH1/2 and ALL cases expressing the TCF3-HLF chimera or TET1 was highly sensitive to PARPi in preclinical studies. These data, along with the warning coming from the observation of cases of therapy-related myeloid malignancies among patients receiving PARPi for solid tumors treatment, indicate that PARPi represents a promising strategy in a personalized medicine setting. The characterization of the clonal and subclonal genetic background and of the DDR functionality is crucial to select acute leukemia patients that will likely benefit of PARPi-based therapeutic regimens.

KIAA1429 regulates the expression of RAB27B in a m6A YTHDF1 axis-dependent manner and promotes the progression of chronic myeloid leukemia, serving as a potential therapeutic target

“…We nally focused on another drug, the PARP inhibitor rucaparib, which has not been used for CML treatment yet. The most recent studies have established that a PARP inhibitor could be used singly and/or in combination with cytotoxic, hypomethylation agents, or targeting drugs for the treatment of acute leukemia [50,51] . Nevertheless, its use in CML treatment has not been reported.…”

The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment

“…Apart from PARP2’functions in hematology, PARP1 and PARP2 are jointly cooperative in sustaining T cell or B cell homeostasis in immune response [ 168 , 169 ]. Given that the available PARP inhibitors in clinic primarily target both PARP1 and PARP2 proteins, the administration of PARPi inevitably leads to hematological adverse events and immune dysfunctions [ 10 , 169 ]. Nowadays, it has been proved that selectively inhibiting PARP1 could bypass such potential side effects [ 170 , 171 ].…”

“…Both PARP1 and PARP2 catalyze poly(ADP)-ribosylation (PARylation), while PARP3 catalyzes mono (ADP)-ribosylation [ 9 ]. So far, the available PARP inhibitors primarily target both PARP1 and PARP2 and the two proteins play an important role in DDR [ 10 ]. Considering PARP1 synthesizes nearly 80% PAR chains in DNA repair pathways for mammalian cells among PARP1 and PARP2, this review specifically refers to PARP1 when we talk about “PARP” proteins in the following sections [ 11 ].…”

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].…”