Clinical use of FLT3 inhibitors in acute myeloid leukemia

Sutamtewagul, Grerk; Vigil, Carlos Enrique

doi:10.2147/ott.s171640

Cited by 39 publications

(42 citation statements)

References 52 publications

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“…A number of FLT3 inhibitors, including gilteritinib, midostaurin, quizartinib, and sorafenib, have been evaluated in clinical trials [12–15]. In 2017, the US Food and Drug Administration (FDA) and European Medicines Agency approved midostaurin for the treatment of adult patients with newly diagnosed AML with FLT3 mutation in combination with standard chemotherapy [16].…”

Section: Introductionmentioning

confidence: 99%

Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells

et al. 2019

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Therapeutic effects of FLT3 inhibitors have been reported in acute myeloid leukemia (AML) with constitutively activating FLT3 mutations, including internal tandem duplication (ITD) and point mutation, which are found in approximately one-third of AML patients. One of the critical issues of treatment with FLT3 inhibitors in FLT3-mutated AML is drug resistance. FLT3 ligand (FL) represents a mechanism of resistance to FLT3 inhibitors, including quizartinib, midostaurin, and sorafenib, in AML cells harboring both wild-type and mutant FLT3 (FLT3wt/FLT3mut). Here, we investigated the effect of FL on the efficacy of gilteritinib, a FLT3 inhibitor, in AML-derived cells in vitro and in mice. In contrast to other FLT3 inhibitors, FL stimulation had little effect on growth inhibition or apoptosis induction by gilteritinib. The antitumor activity of gilteritinib was also comparable between xenograft mouse models injected with FL-expressing and mock MOLM-13 cells. In the FLT3 signaling analyses, gilteritinib inhibited FLT3wt and FLT3-ITD to a similar degree in HEK293 and Ba/F3 cells, and similarly suppressed FLT3 downstream signaling molecules (including ERK1/2 and STAT5) in both the presence and absence of FL in MOLM-13 cells. Co-crystal structure analysis showed that gilteritinib bound to the ATP-binding pocket of FLT3. These results suggest that gilteritinib has therapeutic potential in FLT3-mutated AML patients with FL overexpression.

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Section: Introductionmentioning

confidence: 99%

Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells

et al. 2019

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“…The majority of the mutations is internal tandem duplications (ITD) with only 7% affecting the tyrosine kinase domain (TKD). Several tyrosine kinase (TKI) inhibitors have been studied in FLT3‐mutated AML (including Sunitinib, Lestaurtinib, Sorafenib, Midostaurin, Quizartinib, Gilteritinib, and Crenolanib). It is of note that the FLT3 inhibitors vary significantly in their ability to inhibit other kinases/pathways and to the degree that inhibits the activity of FLT3 mutations.…”

Section: Gilteritinibmentioning

confidence: 99%

Recently approved molecularly targeted therapies in AML

Papadantonakis

Erba

2019

Adv Cell Gene Ther

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Acute myeloid leukemia is a disease for which, until recently few options were available both for the newly diagnosed and relapsed/refractory patients. In the recent years, several new agents have been approved offering patients more options.Encouragingly, the new agents are targeting molecular aberrations/key proteins sparing the patients from the side effects of the intensive chemotherapy regimens. In this review, we highlight the studies leading to approval of Glasdegib, Venetoclax, Enasidenib, Ivosidenib, and Gilteritinib and we highlight key clinical points. We also outline the challenges that the new agents bring in the clinical practice. K E Y W O R D Sacute myeloid leukemia, enasidenib, gilteritinib, glasdegib, ivosidenib, venetoclax

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“…Mutations in FMS-like tyrosine kinase 3 (FLT3, also known as CD135) are present in 30–35% of all AML cases during diagnosis. Therefore, FLT3 kinase domain has become a critical therapeutic target in AML (Sutamtewagul and Vigil, 2018; Wu et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Several highly potent small-molecule inhibitors of FLT3 have been developed, and some are being evaluated in clinical trials, such as sorafenib, crenolanib, and quizartinib (Garcia and Stone, 2017; Sutamtewagul and Vigil, 2018; Wu et al, 2018). However, FLT3 inhibitors have exhibited antineoplastic activity in patients with relapsed or refractory AML, particularly in patients with FLT3 mutations.…”

Section: Introductionmentioning

confidence: 99%

“…However, FLT3 inhibitors have exhibited antineoplastic activity in patients with relapsed or refractory AML, particularly in patients with FLT3 mutations. To date, resistance to FLT3 inhibitors has been associated with different profiles of FLT3 mutations, including N676K, N676D, F691L, G697R, Y842C/H, and D835H/V/F/I/del/Y (Yamamoto et al, 2001; Heidel et al, 2006; Williams et al, 2013; Sutamtewagul and Vigil, 2018). Among the secondary resistance mutations, the gatekeeper mutation F691L conferred high-level resistance to various promising inhibitors, such as quizartinib (Smith et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Insights Into the Resistance Mechanisms of Inhibitors to FLT3 F691L Mutation via an Integrated Computational Approach

et al. 2019

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Research has shown that FMS-like tyrosine kinase 3 (FLT3) may be a vital drug target for acute myeloid leukemia (AML). However, even though the clinically relevant F691L gatekeeper mutation conferred resistance to current FLT3 drug quizartinib, PLX3397 remained unaffected. In this study, the protein–ligand interactions between FLT3 kinase domain (wild-type or F691L) and quizartinib or PLX3397 were compared via an integrated computational approach. The classical molecular dynamics (MD) simulations in conjunction with dynamic cross-correlation (DCC) analysis, solvent-accessible surface area (SASA), and free energy calculations indicated that the resistant mutation may induce the conformational change of αC-helix and A-loop of the FLT3 protein. The major variations were controlled by the electrostatic interaction and SASA, which were allosterically regulated by residues Glu-661 and Asp-829. When FLT3-F691L was bound to quizartinib, a large conformational change was observed via combination of accelerated MD simulations (aMDs), principal component analysis (PCA), and free energy landscape (FEL) calculations. The umbrella sampling (US) simulations were applied to investigate the dissociation processes of the quizartinib or PLX3397 from FLT3-WT and FLT3-F691L. The calculated results suggested that PLX3397 had similar dissociation processes from both FLT3-WT and FLT3-F691L, but quizartinib dissociated more easily from FLT3-F691L than from FLT3-WT. Thus, reduced residence time was responsible for the FLT3-F691L resistance to inhibitors. These findings indicated that both the conformational changes of αC-helix and A-loop and the drug residence time should be considered in the design of drugs so that rational decisions can be made to overcome resistance to FLT3-F691L.

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Clinical use of FLT3 inhibitors in acute myeloid leukemia

Cited by 39 publications

References 52 publications

Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells

Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells

Recently approved molecularly targeted therapies in AML

Insights Into the Resistance Mechanisms of Inhibitors to FLT3 F691L Mutation via an Integrated Computational Approach

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