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

Abstract

// Kozo Nagai 1,* , Lihong Hou 1,* , Li Li 1 , Bao Nguyen 1 , Tessa Seale 1 , Courtney Shirley 1 , Hayley Ma 1 , Mark Levis 1 , Gabriel Ghiaur 1 , Amy Duffield 2 and Donald Small 1,3 1 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA * Kozo Nagai and Lihong Hou contributed equally to this work Correspondence to: Donald Small, email: donsmall@jhmi.edu Keywords : acute myeloid leukemia; FLT3; internal tandem duplication; tyrosine kinase inhibitor; arsenic trioxide Received: July 27, 2018     Accepted: August 02, 2018     Published: August 31, 2018 Abstract Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Arsenic trioxide (ATO, As 2 O 3 ) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and relapsed AML and other hematologic malignances. We explored the feasibility of combining FLT3 TKIs with ATO in the treatment of FLT3/ITD+ leukemias. The combination of FLT3 TKIs with ATO showed synergistic effects in reducing proliferation, viability and colony forming ability, and increased apoptosis in FLT3/ITD+ cells and primary patient samples. In contrast, no cooperativity was observed against wild-type FLT3 leukemia cells. ATO reduced expression of FLT3 RNA and its upstream transcriptional regulators (HOXA9, MEIS1), and induced poly-ubiquitination and degradation of the FLT3 protein, partly through reducing its binding with USP10. ATO also synergizes with FLT3 TKIs to inactivate FLT3 autophosphorylation and phosphorylation of its downstream signaling targets, including STAT5, AKT and ERK. 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.