Arsenic Trioxide and Sorafenib Induce Synthetic Lethality of FLT3-ITD Acute Myeloid Leukemia Cells

Mol Cancer Ther. 2018 Sep;17(9):1871-1880. doi: 10.1158/1535-7163.MCT-17-0298. Epub 2018 Jun 29.

Abstract

Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity, produces an impressive but short-lived remission in FLT3-ITD AML patients. The second, arsenic trioxide (ATO), at therapeutically achievable concentrations, reduces the level of FLT3-ITD and Mcl-1 proteins, and induces apoptosis in leukemic cell lines and in primary cells expressing FLT3-ITD. We linked this relative sensitivity to ATO to low levels of reduced glutathione. While producing proapoptotic effects, ATO treatment also has an unwanted effect whereby it causes the accumulation of the phosphorylated (inactive) form of glycogen synthase kinase 3β (GSK3β), a kinase necessary for apoptosis. When ATO is combined with Sorafenib, GSK3β is activated, Mcl-1 is further reduced, and proapoptotic proteins Bak and Bax are activated. Mice xenografted with FLT3-ITD MOLM13 cell line treated with the Sorafenib/ATO combination have significantly improved survival. This combination has potential to improve the therapeutic outcome of FLT3-ITD-targeted therapy of AML patients. Mol Cancer Ther; 17(9); 1871-80. ©2018 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Arsenic Trioxide / administration & dosage
  • Cell Line, Tumor
  • Humans
  • Kaplan-Meier Estimate
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / genetics
  • Leukemia, Myeloid / pathology
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Sorafenib / administration & dosage
  • Synthetic Lethal Mutations / drug effects*
  • THP-1 Cells
  • Tandem Repeat Sequences / genetics
  • Xenograft Model Antitumor Assays*
  • fms-Like Tyrosine Kinase 3 / genetics*

Substances

  • Sorafenib
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Arsenic Trioxide