SEL120, a potent and specific inhibitor of CDK8 induces complete remission in human patient derived xenograft models of acute myeloid leukemia

Cyclin-dependent kinase 8 inhibitors (CDK8i) have anti-cancer activity in human acute myeloid leukaemia (AML) cell lines both in vitro and in vivo. Activity of CDK8i often involves deregulation of super-enhancer-associated genes in AML cell lines. Previous studies established SEL120 as a specific CDK8 inhibitor active in AML cells with increased STAT1/5 signalling pathways. Differential gene expression analysis demonstrated high enrichment of leukaemia stem cell (LSC) signatures in responding cells, linked to resistance to standard therapies and relapsed disease. Cells sensitive to SEL120 treatment were positive for CD34 and negative for lineage commitment surface markers. SEL120 markedly reduced STAT5 phosphorylation on serine 726 (STAT5 pS726) in sensitive cell lines. Prolonged SEL120 treatment led to significant downregulation of CD34 and induction of lineage commitment markers. Transcriptomic analysis revealed that SEL120 regulated many genes involved in differentiation and apoptosis. We observed synergistic effects of SEL120 with standard of care cytotoxic drugs such as cytarabine. Treatment of AML cells with cytarabine spared many CD34+ cells, which could be effectively eradicated by subsequent treatment with SEL120. Many cell lines which were resistant to SEL120 treatment could be sensitized by concomitant treatment with BH3 mimetic agent ABT-199. Combination of both compounds resulted in potent induction of apoptosis in AML cells in vitro and in vivo. Treatment of mice bearing subcutaneously implanted human leukaemia cell lines resulted in significant tumour growth inhibition, whereas cotreatment with ABT-199 led to complete regressions at doses which were vey well tolerated by animals. Next we have selected patient derived primary AML cells using gene expression signatures identifying SEL120 -responder cell lines. In these cells SEL120 significantly reduced viability, induced apoptosis and lineage commitment. Further, the same cells were implanted into NOD scid gamma mice. Animals succumbed to AML, diagnosed by a significant presence of human CD45/CD34 positive leukaemia cells in a peripheral blood and splenomegaly. Stand-alone treatment with SEL120 resulted in the complete remission of AML cells in a peripheral blood and bone marrow, and reduced spleen weight, without symptoms of compound-related toxicity. These results validate SEL120 as a promising agent in the treatment of AML. Citation Format: Milena Mazan, Eliza Majewska, Michal Mikula, Katarzyna Wiklik, Michal Combik, Aniela Golas, Magdalena Masiejczyk, Elzbieta Fiedor, Anna Polak, Magdalena Cybulska, Aleksandra Grochowska, Michal Kopczynski, Urszula Kuklinska, Zuzanna Sandowska-Markiewicz, Malgorzata Statkiewicz, Agnieszka Paziewska, Michalina Dabrowska, Arkadiusz Bialas, Maciej Mikulski, Renata Windak, Jerzy Ostrowski, Przemyslaw Juszczynski, Krzysztof Brzozka, Tomasz Rzymski. SEL120, a potent and specific inhibitor of CDK8 induces complete remission in human patient derived xenograft models of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1306.