4.7 Article

CCT245718, a dual FLT3/Aurora A inhibitor overcomes D835Y-mediated resistance to FLT3 inhibitors in acute myeloid leukaemia cells

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BRITISH JOURNAL OF CANCER
卷 125, 期 7, 页码 966-974

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DOI: 10.1038/s41416-021-01527-2

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  1. Lahore University of Management Sciences [Fund-253, STG-064]

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The dual inhibitor CCT245718 has potent anti-proliferative activity against FLT3-ITD+ AML cell lines and binds strongly to FLT3-ITD and TKD (D835Y) mutants in vitro. It overcomes TKD-mediated resistance and inhibits both FLT3-ITD and Aurora A activities, leading to cell death through reduced phosphorylation of STAT5, downregulation of survivin, and induction of apoptosis.
Background Activating mutations in the Fms-like tyrosine kinase 3 (FLT3) are among the most prevalent oncogenic mutations in acute myeloid leukaemia. Inhibitors selectively targeting FLT3 kinase have shown promising clinical activity; their success in the clinic, however, has been limited due to the emergence of acquired resistance. Methods CCT245718 was identified and characterised as a dual Aurora A/FLT3 inhibitor through cell-based and biochemical assays. The ability of CCT245718 to overcome TKD-mediated resistance was evaluated in a cell line-based model of drug resistance to FLT3 inhibitors. Results CCT245718 exhibits potent antiproliferative activity towards FLT3-ITD + AML cell lines and strongly binds to FLT3-ITD and TKD (D835Y) mutants in vitro. Activities of both FLT3-ITD and Aurora A are also inhibited in cells. Inhibition of FLT3 results in reduced phosphorylation of STAT5, downregulation of survivin and induction of apoptotic cell death. Moreover, CCT245718 overcomes TKD-mediated resistance in a MOLM-13-derived cell line containing FLT3 with both ITD and D835Y mutations. It also inhibits FLT3 signalling in both parental and resistant cell lines compared to FLT3-specific inhibitor MLN518, which is only active in the parental cell line. Conclusions Our results demonstrate that CCT245718 is a potent dual FLT3/Aurora A inhibitor that can overcome TKD-mediated acquired resistance.

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