Unifying targeted therapy for leukemia in the era of PARP inhibition

Abstract

PARP inhibitors (PARPi) represent a novel class of targeted therapies that have conventionally been used for the treatment of BRCA1/2-mutated solid tumors. PARP1 being an indispensable component of the DNA repair machinery is essential for maintaining genomic integrity. Germline mutations or expression changes in genes compromising homologous recombination (HR)-mediated repair increases dependency on PARP1 and sensitizes these cells to PARP inhibition. Unlike solid tumors, hematologic malignancies do not frequently harbor BRCA1/2 mutations. PARP inhibition as a therapeutic strategy in blood disorders, therefore, did not receive the same importance. However, underlying epigenetic plasticity and leveraging transcriptional dependencies across molecular subtypes of leukemia has invigorated PARP inhibition-guided synthetic lethality in hematologic malignancies. For example, recent studies showing the importance of robust DNA repair machinery in acute myeloid leukemia (AML) increased the evidence of genomic instability associated with leukemia-driven mutations, and compromised repair pathways in certain subgroups of AML has shifted the focus on exploiting PARPi synthetic lethality in leukemia. Single-agent PARPi as well as combination with other targeted therapies has shown promising results in clinical trials involving patients with AML and myelodysplasia. In this study, we evaluated antileukemic potential of PARPi, understood the subtype-dependent differential responses, discussed recent clinical trials, and provided an outlook for future combination therapy strategies. Extensive genetic and epigenetic characterization, utilizing results from completed and ongoing studies will further help to determine specific subset of patients who may respond, and to establish PARPi as a mainstay in leukemia treatment.