LAUSR

Myelodysplastic syndrome (MDS) & Acute Myeloid Leukemia (AML) are hematologic malignancies that arise from a population of aberrant hematopoietic stem cells (HSCs). Overactivated innate immune signaling pathways such as IRAK1, TRAF6, IL1RAP, S100A9 and IL8 have been demonstrated in MDS/AML and play important roles in propagation of disease. IRAK4 (interleukin-1 receptor-associated kinase 4), is a protein kinase involved in signaling innate immune responses and forms a critical signaling complex with IRAK1. To determine its role in disease pathobiology, we analyzed transcriptomic data from CD34+ stem and progenitor cells from 183 MDS patients and found significantly increased expression of IRAK4 in MDS samples belonging to the high risk RAEB category (Refractory anemia with excess of blasts, N=80, P Value To functionally determine the role of IRAK4 in MDS/AML pathogenesis, we utilized CA-4948, a potent, oral, small-molecule inhibitor of IRAK4, to assess the effect of inhibiting IRAK4 catalytic activity. In vitro, CA-4948 blocked downstream NF-κB pathway signaling, including secretion of proinflammatory cytokines, in Toll-like receptor stimulated THP1 leukemic cells. CA-4948 was tested in clonogenic assays from primary MDS and AML samples. MDS and AML are associated with block in differentiation that leads to cytopenias that are the cause of morbidity in these patients. Treatment with CA-4948 led to increased erythroid and myeloid differentiation in a majority of samples. Furthermore, drug treatment led to decreased viability of MDS/AML stem cells (CD34+/CD38-/Lin-ve) In vivo studies using a THP1 leukemia xenograft model in NSG mice demonstrated that CA-4948 was well tolerated and led to significantly decreased disease burden after 6 weeks of treatment. In conclusion, we demonstrate that IRAK4 is upregulated in stem and progenitor cells in MDS and AML and is an adverse prognostic marker. Importantly, a novel, specific, inhibitor of IRAK4 shows preclinical in vitro and in vivo efficacy in MDS and AML models. Citation Format: Gaurav S. Choudhary, Tushar D. Bhagat, Maria Elena S. Samson, Shanisha Gordon, Dagny Von Ahrens, Kith Pradhan, Aditi Shastri, Andrea Pellagatti, Jacqueline Boutlwood, Robert N. Booher, Ulrich Steidl, Amit Verma. Efficacy of novel IRAK4 inhibitor CA4948 in AML and MDS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 127. doi:10.1158/1538-7445.AM2017-127