FLT3 inhibitors: clinical potential in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy that is cured in as few as 15%–40% of cases. Tremendous improvements in AML prognostication arose from a comprehensive analysis of leukemia cell genomes. Among normal karyotype AML cases, mutations in the FLT3 gene are the ones most commonly detected as having a deleterious prognostic impact. FLT3 is a transmembrane tyrosine kinase receptor, and alterations of the FLT3 gene such as internal tandem duplications (FLT3-ITD) deregulate FLT3 downstream signaling pathways in favor of increased cell proliferation and survival. FLT3 tyrosine kinase inhibitors (TKI) emerged as a new therapeutic option in FLT3-ITD AML, and clinical trials are ongoing with a variety of TKI either alone, combined with chemotherapy, or even as maintenance after allogenic stem cell transplantation. However, a wide range of molecular resistance mechanisms are activated upon TKI therapy, thus limiting their clinical impact. Massive research efforts are now ongoing to develop more efficient FLT3 TKI and/or new therapies targeting these resistance mechanisms to improve the prognosis of FLT3-ITD AML patients in the future.

FLT3-ITD Activates RSK1 to Enhance Proliferation and Survival of AML Cells by Activating mTORC1 and eIF4B Cooperatively with PIM or PI3K and by Inhibiting Bad and BIM

“…FLT3 is a receptor-tyrosine kinase expressed on hematopoietic progenitor cells, playing important roles in regulation of proliferation, survival, and differentiation of these cells [1,2]. Internal tandem duplication mutations in the FLT3 juxtamembrane domain (FLT3-ITDs) are the most frequent mutations in acute myeloid leukemia (AML), found in 25-30% of cases and associated with a poor prognosis.…”

“…Point mutations within the FLT3 tyrosine kinase domain (FLT3-TKDs), such as the most prevalent D835Y mutation, are found in 5-10% of patients with AML, whereas their significance on prognosis remains unclear. FLT3-ITD, as well as FLT3-TKD, induces ligand-independent autophosphorylation and activation of the receptor, leading to constitutive activation of various downstream signaling events involving the PI3K/AKT/mTOR and MEK/ERK pathways, as well as STAT5, to promote cytokine-independent cell survival and proliferation [1,2]. The other aberrantly activated tyrosine kinase mutants BCR/ABL and JAK2-V617F also activate these intracellular signaling events constitutively and are involved in leukemogenesis of Ph-positive leukemias, such as chronic myeloid leukemia and Ph-positive acute lymphoblastic leukemia, or Ph-negative myeloproliferative neoplasms, such as polycythemia vera or primary myelofibrosis, respectively [3,4].…”

“…Various tyrosine kinase inhibitors (TKIs) for BCR/ABL, such as imatinib, nilotinib, and dasatinib, have been in clinical use and have demonstrated unprecedented efficacy for treatment for Ph-positive leukemias, whereas the JAK1/JAK2 inhibitor ruxolitinib has been approved for clinical use against myeloproliferative neoplasms with only limited efficacies. Although several TKIs relatively specific for FLT3 are currently under development or in clinical use, clinical trials with these used as a single agent have so far shown only limited efficacies with transient responses because of emergences of resistance mutations, and through other various mechanisms in the case of quizartinib (AC-220) [1]. Therefore, novel strategies to target mutant FLT3 are needed to improve the clinical outcome of AML with FLT3 mutations.…”

“…BH3 mimetics antagonizing antiapoptotic Bcl-2 family members, such as Bcl-2, Bcl-xL, and Mcl-1, are currently in clinical use or under development for treatment for hematological malignancies, including AML [11]. FLT3-ITD directly phosphorylates and, thus, activates STAT5 strongly, which contributes to enhance transforming potentials of FLT3-ITD, at least partly, by inducing expression of PIM serine/threonine kinases [1,2]. We previously reported that FLT3-ITD activates the mTORC1/S6K/4EBP1 pathway cooperatively through the STAT5/PIM and PI3K/AKT pathways in AML cells, which promotes proliferation and survival, as well as therapy resistance to PI3K/AKT inhibitors and proteasome inhibitors, at least partly, by upregulating cap-dependent translation by the eIF4F complex [12][13][14].…”

Molecular Interaction Between the Microenvironment and FLT3/ITD+ AML Cells Leading to the Refractory Phenotype

“…Internal tandem duplication mutations in the FLT3 gene (FLT3/ITD), which are expressed in human acute myeloid leukemia (AML) stem cells, are found in ~30% of patients with AML [3]. FLT3/ITD + AML is one of the most intractable hematological malignancies because of the emergence of resistant clones to FLT3/ITD inhibitors or chemotherapies [3,4]. FLT3/ITD allows ligand-independent activation and phosphorylation of the FLT3 receptor.…”