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.

Keywords: Acute lymphoblastic leukemia; Acute myeloid leukemia; Biomarkers; Clinical trials; DNA damage response; PARP; Preclinical studies; Synthetic lethality.

Fig. 1

Mechanism of action of PARP1 in base excision repair (A) and single-strand DNA nick repair (B)

Fig. 2

Mechanism of action of PARP1 in cNHEJ, aNHEJ and HR repair according to the cell cycle phases

Fig. 3

Genomic alterations of PARP1/2/3 and BRCA1/2 in pediatric AML and ALL TARGET study and adult AML cohorts (Beat AML, TCGA-LAML and NGS-PTL). A Oncoprint of genomic alterations of PARP1, PARP2, PARP3, BRCA1 and BRCA2 acute leukemia cohorts. B Frequency and type of genomic alterations

Fig. 4

Schematic representation of PARPi mechanism of action. A SSBs are normally identified and repaired by PARP1 and B the addition of a PARPi compromises the repair and the SSB is converted in DSBs. C PARP1 inhibitors can generate PARP-DNA complexes that during DNA replication can promote DNA replication forks collapse and, consequently, the generation of DSBs. The fate of DSBs depends on HR proficiency of the cancer cells. If the cells are HR proficient, DSBs are repaired and the cells survive, on the contrary, DSBs are not repaired, damages accumulate during replication until cancer cells’ death

Fig. 5

Selective vulnerabilities of PARP inhibitors in AML and ALL. A The known molecular alterations that modify the sensitivity of AML cells to PARPi are represented on the two sides of the balance. Green and red indicate molecular alterations enhancing and hampering PARPi sensitivity, respectively. B Schematic representation of HR and NHEJ repair pathways in response to DSBs. In the scheme, red and green arrows represent the level of expression of different genes associated with AML subtypes (low and high expression, respectively). C The known molecular alterations that modify the sensitivity of ALL cells to PARPi are represented on the two sides of the balance. Green indicates molecular alterations enhancing PARPi sensitivity. To date, no molecular alterations hampering PARP sensitivity have been identified in ALL