WEE1 and PARP-1 play critical roles in myelodysplastic syndrome (MDS): A novel approach to targeted MDS therapy

Abstract

Abstract Background Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder defined by cytopenia and is associated with an increased risk of transformation to acute myeloid leukemia (AML). The outcome of MDS is poor, and as a result, alternative therapeutic approaches are needed to improve survival. The inhibition of the DNA damage response pathway, including poly (ADP-ribose) polymerase-1 (PARP-1), has been approved to treat several cancers, and WEE1 is overexpressed in many cancers. Therefore, a WEE1 inhibitor in combination with a PARP-1 inhibitor could inhibit the proliferation of MDS and AML. Methods We analyzed whether WEE1 was regulated in the progression of MDS and AML. We also evaluated the efficacy of MK-1775 (WEE1 inhibitor) and talazoparib (PARP-1 inhibitor). Results WEE1 expression was higher in the AML cells than in the MDS cells. However, PARP-1 expression remained unchanged. MK-1775 or talazoparib alone inhibited MDS and AML cells after 72 hours, and cellular cytotoxicity and caspase 3/7 activity were increased. The combined use of MK-1775 and talazoparib produced superior efficacy than either drug alone, and SKM-1 colony formation was reduced. Significant cell populations in the sub-G1 phase were shown in the cell-cycle analyses. Additionally, γ-H2AX expression and caspase 3 activity were increased. The combined treatment also changed the mitochondrial membrane potential. Conclusions A combination of WEE1 and PARP-1 inhibition enhanced the efficacy and is proposed as a new therapeutic option for patients with MDS or AML. Our findings have clinical implications for a potential novel therapeutic strategy for MDS patients.