Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia

Abstract

FMS-like tyrosine kinase 3 (FLT3) mutations are genetic changes found in approximately thirty percent of patients with acute myeloid leukemia (AML). FLT3 mutations in AML represent a challenging clinical scenario characterized by a high rate of relapse, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The advent of FLT3 tyrosine kinase inhibitors (TKIs), such as midostaurin and gilteritinib, has shown promise in achieving complete remission. However, a substantial proportion of patients still experience relapse following TKI treatment, necessitating innovative therapeutic strategies. This review critically addresses the current landscape of TKI treatments for FLT3+ AML, with a particular focus on gilteritinib. Gilteritinib, a highly selective FLT3 inhibitor, has demonstrated efficacy in targeting the mutant FLT3 receptor, thereby inhibiting aberrant signaling pathways that drive leukemic proliferation. However, monotherapy with TKIs may not be sufficient to eradicate AML blasts. Specifically, we provide evidence for integrating gilteritinib with mammalian targets of rapamycin (mTOR) inhibitors and interleukin-15 (IL-15) complexes. The combination of gilteritinib, mTOR inhibitors, and IL-15 complexes presents a compelling strategy to enhance the eradication of AML blasts and enhance NK cell killing, offering a potential for improved patient outcomes.

Keywords: NK cells; acute myeloid leukemia (AML); gilteritinib; mTOR inhibitors; rapamycin.

Figure 3

(A) Pro-survival signaling pathways in AML and (B) proposed inhibition mechanisms using FLT3 and mTOR inhibitors. FLT3 mutations, such as ITD and TKD, lead to dysregulation of the FLT3 pathway, causing constitutive activation. Gilteritinib inhibits FLT3 at the ITD in the juxtamembrane domain and the TKD mutation in TKD2. Small-molecule inhibitors of the mTOR complexes include dual PI3K/mTORi, allosteric mTORi, and ATP competitive inhibitors of mTORC1 and mTORC2. The red arrow denotes elevated Akt phosphorylation, and the blunt-end red lines represent negative regulation. Black blunted ends represent mechanisms of therapeutic intervention [113,114]. These figures were generated using Biorender.

Figure 3

(A) Pro-survival signaling pathways in AML and (B) proposed inhibition mechanisms using FLT3 and mTOR inhibitors. FLT3 mutations, such as ITD and TKD, lead to dysregulation of the FLT3 pathway, causing constitutive activation. Gilteritinib inhibits FLT3 at the ITD in the juxtamembrane domain and the TKD mutation in TKD2. Small-molecule inhibitors of the mTOR complexes include dual PI3K/mTORi, allosteric mTORi, and ATP competitive inhibitors of mTORC1 and mTORC2. The red arrow denotes elevated Akt phosphorylation, and the blunt-end red lines represent negative regulation. Black blunted ends represent mechanisms of therapeutic intervention [113,114]. These figures were generated using Biorender.

Figure 1

Structure of the FLT3 receptor in the inactive and active/mutated forms and associated downstream. FLT3 ligand (FLT3L) binding to the FLT3 ligand causes receptor dimerization and activation of downstream signaling pathways. Mutated FLT3 is constitutively active even in the absence of FLT3L. Constitutive activation causes perpetual activation of downstream signaling through the JAK/STAT5/PIM-1, RAS/MEK/MAPK/ERK, and PI3K/Akt/mTOR pathways, causing unchecked survival and growth of AML blasts. The purple and blue circles represent the Extracellular domain of the FLT3 receptor. The yellow circle with a P inside represents a phosphate. Arrows indicate the downstream pathways that are activated. The figure was generated using Biorender (https://www.biorender.com/).

Figure 2

Overview of the four complexes found in the mTOR pathway. Specific components of each complex and their potential physiological functions are denoted in the figure [97]. While all complexes contain mTOR as part of the central structure, they differ in their composition of activating proteins. mTORC1 contains Raptor, Deptor, mLST8, and PRAS40. mTORC2 contains Rictor, Deptor, mLST8, MSIN1, and Protor. Not much is known about mTORC3; however, it contains ETV7 in its structure. mTORC4, like mTORC1 and mTORC2, contains mLST8, but also mEAK-7 and DNA-PKcs as part of its structure. Unchecked signaling through these complexes causes tumorigenesis and unchecked survival and proliferation. The figure was generated using Biorender.

Figure 4

T cell versus NK cell engagement with AML blasts. The HLA-E peptide complex binds to inhibitory receptor NKG2A/CD94 or activating receptor NKG2C/CD94 on the NK surface. The activating receptor NKG2D binds to ULBPs and MICA/MICB. The figure was generated using Biorender.