Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms

Kampa-Schittenhelm, Kerstin M; Heinrich, Michael C.; Akmut, Figen; Döhner, Hartmut; Döhner, Konstanze; Schittenhelm, Marcus M

doi:10.1186/1476-4598-12-19

Cited by 94 publications

(76 citation statements)

References 45 publications

(55 reference statements)

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“…This is true in acute myeloid leukemia (AML), where patients may harbor somatic mutations in a number of potential oncogenes, including FLT3, MLL, TYK2, FGFR1, PDGFRA, IDH1, DNMT3A, affecting expression of downstream signaling for example through PIM kinases (5-7). FLT3 internal tandem duplications (FLT3-ITD) and PIM overexpression are associated with poor prognosis in AML patients, motivating the development of small molecule inhibitors targeting these proteins (8,9). Incomplete signaling inhibition or the presence of multiple molecular alterations that reduce a tumors dependency on any one target may result in drug resistance (10,11).…”

Section: Introductionmentioning

confidence: 99%

Cell-Specific Computational Modeling of the PIM Pathway in Acute Myeloid Leukemia

et al. 2017

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Personalized therapy is a major goal of modern oncology, as patient responses vary greatly even within a histologically defined cancer subtype. This is especially true in acute myeloid leukemia (AML), which exhibits striking heterogeneity in molecular segmentation. When calibrated to cell-specific data, executable network models can reveal subtle differences in signaling that help explain differences in drug response. Furthermore, they can suggest drug combinations to increase efficacy and combat acquired resistance. Here, we experimentally tested dynamic proteomic changes and phenotypic responses in diverse AML cell lines treated with pan-PIM kinase inhibitor and fms-related tyrosine kinase 3 (FLT3) inhibitor as single agents and in combination. We constructed cell-specific executable models of the signaling axis, connecting genetic aberrations in FLT3, tyrosine kinase 2 (TYK2), platelet-derived growth factor receptor alpha (PDGFRA), and fibroblast growth factor receptor 1 (FGFR1) to cell proliferation and apoptosis via the PIM and PI3K kinases. The models capture key differences in signaling that later enabled them to accurately predict the unique proteomic changes and phenotypic responses of each cell line. Furthermore, using cell-specific models, we tailored combination therapies to individual cell lines and successfully validated their efficacy experimentally. Specifically, we showed that cells mildly responsive to PIM inhibition exhibited increased sensitivity in combination with PIK3CA inhibition. We also used the model to infer the origin of PIM resistance engineered through prolonged drug treatment of MOLM16 cell lines and successfully validated experimentally our prediction that this resistance can be overcome with AKT1/2 inhibition.

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Section: Introductionmentioning

confidence: 99%

Cell-Specific Computational Modeling of the PIM Pathway in Acute Myeloid Leukemia

et al. 2017

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“…In one study, an isogenic BaF3 cell line model system was created. This cell line was transfected with various isoforms of KIT, FLT3, or BCR/ABL and was developed to better understand the differences in mutant isoforms with regard to activity of AC220 (Kampa-Schittenhelm et al 2010). While potent inhibition of FLT3 was observed as expected, as in other FLT3 inhibitors, data reveal the development of unique resistance pattern towards some domain 2 mutations, and the authors suggest possibly checking mutational screening analysis to be performed prior to FLT3 inhibition therapy.…”

Section: Emergence Of Ac220-resistant Flt3 Kinase Domain Mutationsmentioning

confidence: 94%

FLT3-ITD. Clinical (Sorafenib/AC220)

Cortes

Pemmaraju

2014

Targeted Therapy of Acute Myeloid Leukemia

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A plethora of new molecular abnormalities has been identified to be associated with acute myelogenous leukemia (AML). These markers have contributed to a more accurate prognostic stratification of these patients, and have nurtured hopes for effective targeted therapies. One such abnormality is the FMS-like tyrosine kinase 3, or FLT3 gene mutation, present in approximately 30 % of AML patients. The presence of the FLT3 internal tandem duplication (FLT3-ITD) confers a poorer prognosis with higher risk of relapse for this subset of AML patients. Rapid development of a large number of FLT3 tyrosine kinase inhibitors (TKIs) has enabled an exciting era of research and treatment for patients with these abnormalities. The expectation is that FLT3 inhibition may offer improvements in outcomes in this poor prognosis group of patients. Early data suggest that this promise may be materializing for patients. This chapter will focus on two of these FLT3 inhibitors, sorafenib (Nexavar®) and AC220 (quizartinib).

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“…71 Quizartinib was developed expressly to be an FLT3 inhibitor and is more potent and specific in vitro than the broadly targeted agents such as midostaurin, lestaurtinib and sorafenib. 70 Pharmacokinetic data from a dose-escalation study showed that quizartinib is well tolerated at doses up to 450 mg and has good oral bioavailability and a long effective half-life (1.5 days) and that quizartinib exposure is maintained between doses in patients with AML.…”

Section: Quizartinib (Ac220)mentioning

confidence: 99%

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

2012

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Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/ pharmacodynamic profile. Novel combination regimens are also discussed.

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Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms

Cited by 94 publications

References 45 publications

Cell-Specific Computational Modeling of the PIM Pathway in Acute Myeloid Leukemia

Cell-Specific Computational Modeling of the PIM Pathway in Acute Myeloid Leukemia

FLT3-ITD. Clinical (Sorafenib/AC220)

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

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