Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia cells through reduced expression of FLT3

The cover for issue 68 of Oncotarget features Figure 6G, "Summary of the mechanisms for the synergistic combination of ATO and FLT3 TKIs in FLT3 mutant AML cells," by Nagai, et al.

The research team explored the feasibility of combining FLT3 TKIs with ATO in the treatment of FLT3/ITD+ leukemias. Furthermore, ATO combined with sorafenib, a FLT3 TKI, in vivo reduced growth of FLT3/ITD+ leukemia cells in NSG recipients. In conclusion, these results suggest that ATO is a potential candidate to study in clinical trials in combination with FLT3 TKIs to improve the treatment of FLT3/ITD+ leukemia.

Dr. Donald Small from the Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA and the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA said, "Over the last few decades, the outcome of patients with AML has been improved by development of intensive chemotherapy, risk-based stratification, and stem cell transplantation."

"Over the last few decades, the outcome of patients with AML has been improved by development of intensive chemotherapy, risk-based stratification, and stem cell transplantation"

- Dr. Donald Small, Department of Oncology, Johns Hopkins University School of Medicine & the Department of Pediatrics, Johns Hopkins University School of Medicine

Figure 6: ATO induces poly-ubiquitination and degradation of FLT3. A., B. TF-1/ITD-Ub cells were treated with ATO or sorafenib followed by immunoprecipitation with FLT3 antibody and Western blotting. Signal intensity of Ubiquitin relative to FLT3 vs. control is shown. C., D., E. TF1/WT-Ub or TF1/ITD-Ub cells were treated with 5μM MG-132 for 1 hour followed by 4-hour treatment with ATO or sorafenib. Western blotting was conducted following immunoprecipitation with anti-FLT3 antibodies or using whole cell lysate (WCL). F. TF1-ITD-Ub cells were treated with 5μM MG-132 for 1 hour followed by 17-AAG and /or ATO treatment for 4 hours. Cell lysates were immunoprecipitated with anti-FLT3 antibodies followed by Western blotting for FLT3 or Ubiquitin proteins. G. Summary of the mechanisms for the synergistic combination of ATO and FLT3 TKIs in FLT3 mutant AML cells.

Therefore, ATO has also been tested in a number of clinical trials for the treatment of non-APL AML with the demonstration of some clinical activity. The clinical application of ATO has been somewhat limited by its toxicity to heart, liver, kidney and the nervous system, especially the cardiac toxicity caused by high concentrations of ATO.

Recently, several studies have reported the synergistic effects of ATO and FLT3 TKIs on FLT3 mutant leukemia cells. Here they investigate the feasibility of combining ATO with FLT3 TKIs, with a specific focus on understanding ATOs effect on the degradation of mutant FLT3 protein, as a strategy to increase the efficacy of FLT3 TKIs in the aim to improve the treatment of FLT3/ITD+ leukemia.

The Donald Small research team concluded, "This report has demonstrated that ATO exerts synergistic anti-leukemic effects together with FLT3 TKI through down regulation of FLT3 expression."

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DOI - https://doi.org/10.18632/oncotarget.25972

Full text - https://www.oncotarget.com/article/25972/text/

Correspondence to - Donald Small - donsmall@jhmi.edu

Keywords - acute myeloid leukemia, FLT3, internal tandem duplication, tyrosine kinase inhibitor, arsenic trioxide

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