CK2 inhibitor, CX-4945, enhances BH3 priming and promotes apoptosis of venetoclax-resistant AML by targeting antiapoptotic proteins

Acute myeloid leukemia (AML), the most common hematologic malignancy, generally has a poor prognosis. Despite initial favorable responses to the BCL2 inhibitor venetoclax (VEN), remission is transient, and AML is eventually fatal. Resistance to VEN is primarily due to the overexpression of anti-apoptotic proteins, including MCL-1, BCL2L1 (BCL-XL), and BCL2A1. Casein kinase II (CK2) is a serine-threonine kinase and a known suppressor of apoptosis. We and others have reported that protein kinase CK2 activity is high in leukemic stem cells (LSCs) and associated with resistance to chemotherapy. We have shown that the selective CK2 inhibitor, CX-4945, suppresses BCL-XL and has a significant anti-tumor effect in AML preclinical models. CK2 expression and activity are high in venetoclax-resistant AML (VR-AML) cell lines. Genetic and pharmacological inhibition of CK2 significantly altered VR-AML gene signature, decreased MCL-1 protein level, increased BH3 priming and sensitized VR-AML cells to apoptosis. More importantly, CX-4945 selectively targeted LSCs (CD34+CD38-) and chemoresistant (CD123+CD47+) subpopulation in VR-AML. CX-4945 combined with VEN decreased leukemia burden and prolonged the survival of VR-AML cell line-derived and patient-derived xenografts compared to either drug alone. The combinatorial treatment was well tolerated in mice without additional myelosuppression or organ toxicity. CX-4945 (silmitasertib) is being tested in several early-phase clinical trials against adult and pediatric cancers. These preclinical results support the use of CX-4945 in combination with VEN to overcome resistance to apoptosis and re-sensitize VR-AML to chemotherapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/696284v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@6a902forg.highwire.dtl.DTLVardef@2028f5org.highwire.dtl.DTLVardef@160fd4dorg.highwire.dtl.DTLVardef@95da53_HPS_FORMAT_FIGEXP M_FIG C_FIG