Drug resistance in mutant FLT3-positive AML

Abstract

Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…29,64 Mutant receptors such as Fms-like tyrosine kinase may induce Foxo-3a inactivation, which can lead to resistance to Fms-like tyrosine kinase inhibitors and result in a poor prognosis. 128,129 A diagram illustrating some of the effects of the PI3K/PTEN/Akt/mTOR pathway on apoptosis and drug resistance is presented in Figure 4.…”

Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia

“…FLT3 is a class III receptor tyrosine kinase, which frequently carries mutations in patients with acute myeloid leukemia (AML) resulting in constitutive activation. 17 It has an important role in the homeostasis of DCs, and its ligand, FLT3L, has been used in several studies to activate these cells in vitro and in vivo. 18 --22 Thus, during characterization of SDIEMmodified FLT3 antibodies we put particular emphasis on the evaluation of antibody specificity and toxicity towards DCs and hematopoietic stem cells in addition to the exploration of ADCC activity.…”

Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy

“…115 Mutant receptors such as Flt-3 may induce Foxo-3a inactivation, which can lead to resistance to Flt-3 inhibitors and result in a poor prognosis. 51,117,118 Recently, it was demonstrated that Foxo-3a is inactive in AML cells and is localized in the cytoplasm. 119 Treatment of AMLs with MEK and PI3K/Akt inhibitors did not result in the nuclear translocation of Foxo-3a where it could potentially induce cell cycle inhibitory and apoptotic genes.…”