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|Ref Type||Journal Article|
|Authors||Reiter K, Polzer H, Krupka C, Maiser A, Vick B, Rothenberg-Thurley M, Metzeler KH, Dörfel D, Salih HR, Jung G, Nößner E, Jeremias I, Hiddemann W, Leonhardt H, Spiekermann K, Subklewe M, Greif PA|
|Title||Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia.|
|Abstract Text||The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in this setting as they are associated with unfavorable prognosis. Because of sequence-dependent protein conformational changes FLT3-ITD tends to autophosphorylate and displays a constitutive intracellular localization. Here, we analyzed the effect of tyrosine kinase inhibitors (TKIs) on the localization of the FLT3 receptor and its mutants. TKI treatment increased the surface expression through upregulation of FLT3 and glycosylation of FLT3-ITD and FLT3-D835Y mutants. In T cell-mediated cytotoxicity (TCMC) assays, using a bispecific FLT3 × CD3 antibody construct, the combination with TKI treatment increased TCMC in the FLT3-ITD-positive AML cell lines MOLM-13 and MV4-11, patient-derived xenograft cells and primary patient samples. Our findings provide the basis for rational combination of TKI and FLT3-directed immunotherapy with potential benefit for FLT3-ITD-positive AML patients.|
|Molecular Profile||Treatment Approach|
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|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
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|FLT3 exon 14 ins FLT3 LOH||acute myeloid leukemia||sensitive||Quizartinib||Preclinical - Cell culture||Actionable||In a preclinical study, Quizartinib (AC220) inhibited proliferation of a acute myeloid leukemia cell line harboring a FLT3-ITD mutation with FLT3 loss of heterozygosity (PMID: 28895560).||28895560|
|FLT3 exon 14 ins||acute myeloid leukemia||sensitive||FLT3/CD3 Fabsc antibody||Preclinical - Cell culture||Actionable||In a preclinical study, treatment of an acute myeloid leukemia (AML) cell lines or patient-derived xenograft (PDX)-derived AML cells harboring a heterozygous FLT3-ITD mutation with a Fabsc FLT3/CD3 bi-specific antibody resulted in near complete eradication of AML cells in culture (PMID: 28895560).||28895560|
|FLT3 exon 14 ins FLT3 LOH||acute myeloid leukemia||sensitive||FLT3/CD3 Fabsc antibody + Quizartinib||Preclinical - Cell culture||Actionable||In a preclinical study, treatment with the combination of Quizartinib (AC220) and an Fabsc FLT3/CD3 bi-specific antibody resulted in increased cytotoxicity over either agent alone in an acute myeloid leukemia cell line and patient-derived xenograft (PDX)-derived AML cells with a FLT3-ITD mutation and FLT3 loss of heterozygosity, leading to near complete eradication of AML cells in culture (PMID: 28895560).||28895560|
|FLT3 exon 14 ins||acute myeloid leukemia||sensitive||Quizartinib||Preclinical - Cell culture||Actionable||In a preclinical study, Quizartinib (AC220) inhibited proliferation of several acute myeloid leukemia cell lines harboring different FLT3-ITD mutations in culture (PMID: 28895560).||28895560|