Abstract 3554: CCT137690, a dual inhibitor of Aurora and FLT3 kinases, sensitizes FLT3-ITD positive acute myeloid leukemia and overcomes resistance to selective FLT3-inhibition
Authors: Moore Andrew S. , Faisal Amir , Bavetsias Vassilios , Sun Chongbo , Atrash Butrus , Valenti Melanie , de Haven Brandon Alexis , Avery Sian , de Castro David Gonzalez , Raynaud Florence I. , Workman Paul , Pearson Andrew DJ , Blagg Julian , Eccles Suzanne A. , Linardopoulos Spiros 
Published: June 2012

Abstract
The Aurora kinases are a family of serine-threonine kinases that play key roles in different stages of mitosis. Over-expression of Aurora kinases has been demonstrated in a range of malignancies including leukemia. Aurora kinase inhibitors are emerging as promising agents in the treatment of acute myeloid leukemia (AML) with a number of compounds currently being assessed in clinical trials (Moore AS et al, Leukemia 2010). CCT137690, an imidazo[4,5-b]pyridine derivative discovered at our Institute, is an orally bioavailable, potent, pan-Aurora and FLT3 inhibitor. CCT137690 showed in vitro and in vivo activity in human colon cancer cell lines and xenograft models (Bavetsias V et al, J Med Chem 2010). Here we report the in vitro and in vivo activity of CCT137690 in FLT3-ITD positive AML and demonstrate that CCT137690 overcomes resistance to the selective FLT3 inhibitor MLN518. In cellular assays using FLT3-ITD positive MOLM-13 cells, CCT137690 inhibits autophosphorylation of Aurora A and Aurora B kinases and phosphorylation of histone H3, a direct target of Aurora B kinase. CCT137690 also inhibits autophosphorylation of FLT3 and its downstream targets phospho-STAT5 and phospho-p44/42 MAPK. Dual inhibition of Aurora and FLT3 kinases in FLT3-ITD positive AML with CCT137690 induces apoptosis and results in a unique cell cycle profile with cells accumulating in G2/M. When given orally to athymic mice, CCT137690 achieved target modulation and potently inhibited the growth of subcutaneous MOLM-13 xenografts, with no obvious toxicity or loss of body weight. Inhibition of MOLM-13 xenograft growth was more pronounced with CCT137690 compared to the selective FLT3 inhibitor MLN518, suggesting that dual inhibition of Aurora and FLT3 kinases may have advantages compared to selective FLT3 inhibition alone. To assess whether dual Aurora-FLT3 inhibition with CCT137690 could overcome FLT3-inhibitor resistance, we successfully cultured MOLM-13 cells in the presence of increasing concentrations of MLN518. Although resistant to MLN518, these cells maintained sensitivity to dual Aurora-FLT3 inhibition with CCT137690. The potent preclinical activity of CCT137690 in FLT3-ITD positive AML models supports the growing body of evidence that dual pan-Aurora and FLT3 kinase inhibitors may be of benefit in the high-risk group of patients with FLT3-ITD positive AML, including those with FLT3-inhibitor resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3554. doi:10.1158/1538-7445.AM2011-3554