Combined Targeting of BET Family Proteins and BCL2 Is Synergistic in Acute Myeloid Leukemia Cells Overexpressing S100A8 and S100A9

摘要: Background The 5-year survival rate for acute myeloid leukemia (AML) remains poor with most patients succumbing to relapse or refractory disease. Recently, the BCL2 specific inhibitor venetoclax has shown promising anti-leukemia activity in high-risk AML patients. Most patients, however, ultimately develop resistance monotherapy and novel combination treatments are needed no other therapy options available. In this study we identified high expression of calcium binding protein S100A8/S100A9 be associated looked drug combinations overcome patient samples overexpressing S100A8 S100A9. Methods Gene was assessed by RNA sequencing validated qPCR. enrichment analysis performed on differentially expressed genes between highly sensitive (n=3) resistant (n=4) samples. Sensitivity derived mononuclear cells 304 different small molecule inhibitors measuring cell viability after 72 h incubation 5 concentrations (1-10,000 nM) using CellTiter-Glo (CTG) assay. A sensitivity score (DSS) calculated based a modified area under dose response curve calculation. Drug studies were lines confirmed primary (n=15). Data analyzed Zero Interaction Potency (ZIP) model considering dose-response matrix where two drugs tested at 8 serially diluted manner. Statistical dependence gene data Pearson9s correlation coefficient modelling. Results Venetoclax found overexpress related immune responses including inflammatory proteins S100A9 upregulated sub-group somatic mutations DNA methylation IDH2 TET2 chromatin modifier ASXL1. Functional S100 insensitive (NOMO-1, SKM-1 SHI-1) whereas (MOLM-13, Kasumi-1 ML-2) did not express proteins. Integrated ex vivo indicated positive BET (birabresib), PI3K (TG100-115) MEK1/2 (AZD8330). contrast, FLT3 quizartinib negatively correlated expression. Subsequently, combined positively correlating efficacy these From that birabresib able treatment. BCL2/BET synergistic NOMO-1 SKM-1, which high-levels (Figure 1A). Efficacy level genes. Nine 11 venetoclax/birabresib 1B-C), synergy observed 3 4 low Conclusions abundant prognosis (Edgeworth et al, J Biol Chem. 1991; Nicolas Leukemia 2011). vitro analyses AML, is correlative venetoclax. correlates birabresib. Interestingly, our showed act synergistically may beneficial should further preclinical clinical investigations. Disclosures Porkka:Celgene: Honoraria, Research Funding; Novartis: Funding. Heckman:Orion Pharma: Celgene: