FLT3

Official Full Name

fms related receptor tyrosine kinase 3

Organism

Homo sapiens

GeneID

2322

Background

This gene encodes a class III receptor tyrosine kinase that regulates hematopoiesis. This receptor is activated by binding of the fms-related tyrosine kinase 3 ligand to the extracellular domain, which induces homodimer formation in the plasma membrane leading to autophosphorylation of the receptor. The activated receptor kinase subsequently phosphorylates and activates multiple cytoplasmic effector molecules in pathways involved in apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. Mutations that result in the constitutive activation of this receptor result in acute myeloid leukemia and acute lymphoblastic leukemia. [provided by RefSeq, Jan 2015]

Synonyms

FLK2; STK1; CD135; FLK-2;

Bio Chemical Class

Kinase

Protein Sequence

MPALARDGGQLPLLVVFSAMIFGTITNQDLPVIKCVLINHKNNDSSVGKSSSYPMVSESPEDLGCALRPQSSGTVYEAAAVEVDVSASITLQVLVDAPGNISCLWVFKHSSLNCQPHFDLQNRGVVSMVILKMTETQAGEYLLFIQSEATNYTILFTVSIRNTLLYTLRRPYFRKMENQDALVCISESVPEPIVEWVLCDSQGESCKEESPAVVKKEEKVLHELFGTDIRCCARNELGRECTRLFTIDLNQTPQTTLPQLFLKVGEPLWIRCKAVHVNHGFGLTWELENKALEEGNYFEMSTYSTNRTMIRILFAFVSSVARNDTGYYTCSSSKHPSQSALVTIVEKGFINATNSSEDYEIDQYEEFCFSVRFKAYPQIRCTWTFSRKSFPCEQKGLDNGYSISKFCNHKHQPGEYIFHAENDDAQFTKMFTLNIRRKPQVLAEASASQASCFSDGYPLPSWTWKKCSDKSPNCTEEITEGVWNRKANRKVFGQWVSSSTLNMSEAIKGFLVKCCAYNSLGTSCETILLNSPGPFPFIQDNISFYATIGVCLLFIVVLTLLICHKYKKQFRYESQLQMVQVTGSSDNEYFYVDFREYEYDLKWEFPRENLEFGKVLGSGAFGKVMNATAYGISKTGVSIQVAVKMLKEKADSSEREALMSELKMMTQLGSHENIVNLLGACTLSGPIYLIFEYCCYGDLLNYLRSKREKFHRTWTEIFKEHNFSFYPTFQSHPNSSMPGSREVQIHPDSDQISGLHGNSFHSEDEIEYENQKRLEEEEDLNVLTFEDLLCFAYQVAKGMEFLEFKSCVHRDLAARNVLVTHGKVVKICDFGLARDIMSDSNYVVRGNARLPVKWMAPESLFEGIYTIKSDVWSYGILLWEIFSLGVNPYPGIPVDANFYKLIQNGFKMDQPFYATEEIYIIMQSCWAFDSRKRPSFPNLTSFLGCQLADAEEAMYQNVDGRVSECPHTYQNRRPFSREMDLGLLSPQAQVEDS

Open

Disease

Acute laryngitis/tracheitis, Acute myeloid leukaemia, Alzheimer disease, Bone/articular cartilage neoplasm, Brain cancer, Chronic myelomonocytic leukaemia, Chronic pain, Colorectal cancer, Diffuse large B-cell lymphoma, Human immunodeficiency virus disease, Idiopathic interstitial pneumonitis, Inflammatory arthropathy, Leukaemia, Lung cancer, Malignant haematopoietic neoplasm, Mastocytosis, Mature B-cell lymphoma, Multiple myeloma, Myeloproliferative neoplasm, Ovarian cancer, Peritoneal cancer, Phakomatoses/hamartoneoplastic syndrome, Psoriasis, Solid tumour/cancer, Transplanted organ/tissue, Virus infection

Approved Drug

9 +

Clinical Trial Drug

19 +

Discontinued Drug

3 +

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Detailed Information

The FMS-like tyrosine kinase 3 (FLT3) gene is located on chromosome 13q12. It belongs to the receptor tyrosine kinase (RTK) family that also comprises FMS, KIT, and PDGFR, among other receptors that play an important role in the regulation of hematopoiesis. The binding of FLT3 ligand to its extracellular domain activates downstream signaling pathways such as MAPK and PI3K/protein kinase B-signals responsible for survival, maturation, and proliferation of hematopoietic cells. The FLT3 receptor is overexpressed in most acute leukemias. It is mutated in more than one-third of acute myeloid leukemia (AML) cases, representing one of the most prevalent molecular genetic alterations, which has proved to be an attractive therapeutic target.

Figure 1. FLT3 activation pathway. (El Fakih R, et al., 2018)

FLT3 Mutations in AML

FLT3 mutations are involved in clonal evolution of AML and represent a second-hit driver by cooperation with other somatic intrinsic events. Mutations of FLT3 are found in about 30% of newly diagnosed AML cases and occur as either internal tandem duplications (ITDs) (approximately 25%) or point mutations in the tyrosine kinase domain (TKD) (7-10%). FLT3-ITD appears in the form of a replicated sequence in the juxtamembrane domain and/or TKD1 of the FLT3 receptor and varies in location and length within these domains. Both FLT3-ITD and FLT3-TKD mutations constitutively activate FLT3 kinase activity, leading to proliferation and survival of AML.

ITD of the FLT3 receptor gene invariably result in the constitutive activation of the receptor-tyrosine kinase (RTK) and its downstream signaling effectors, such as RAS/RAF/MEK/ERK kinases, PI3-kinase and STAT5. Thus, altered mechanisms of cellular proliferation and apoptosis promote cell survival thereby conferring a substantial growth advantage to leukemic stem and progenitor cells. From a clinical point of view, this frequently translates into a higher percentage of blood and bone marrow blasts, and a decrease in overall survival primarily due to a high relapse rate. Lines of evidence show that the allelic burden plays a pivotal role in predicting the level of 'FLT3 addiction' and clinical outcome. For instance, Pratz et al. suggested that low allelic burden FLT3/ITD AML, which appears to more commonly present at the time of initial diagnosis, is less responsive to FLT3 inhibition compared with high allelic burden FLT3/ITD AML, a disease more frequently diagnosed at the time of relapse.

FLT3 Inhibitors in AML

In view of the established pathobiological and prognostic role that FLT3-ITD mutations play in AML, mutant FLT3 is an attractive therapeutic target for leukemia-directed therapies. Currently, several FLT3 inhibitors have been developed and evaluated in clinical trials. These agents work largely through competitive inhibition of ATP-binding sites in the FLT3 receptor, leading to cell cycle arrest and differentiation. Besides, FLT3 tyrosine kinase inhibitors (TKIs) vary in their ability to target non-FLT3 signaling pathways, which influences both the tolerability and the efficacy of different agents. For instance, first-generation FLT3 inhibitors are less specific for FLT3 and have broad kinome profiles with more off-target toxicities. In contrast, second-generation FLT3 inhibitors are more specific and potent at inhibiting FLT3 with narrower kinome profiles. These next-generation inhibitors have greater specificity for FLT3 and higher potency (logarithmically lower half-maximal inhibitory concentration) than multitargeted TKIs.

FLT3 inhibitors have shown promising efficacies in aggressive AML. However, the duration of the clinical response is short due to the rapid development of resistance. Novel next-generation FLT3 inhibitors are being actively developed to concur the resistance. Combining FLT3 inhibitors with other targeted agents are additional areas of investigation to reduce resistance to current FLT3 inhibitors.

References:

Konig H, Levis M. Targeting FLT3 to treat leukemia. Expert opinion on therapeutic targets, 2015, 19(1): 37-54.
Antar A I, et al. FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions. Leukemia, 2020: 1-15.
Larrosa-Garcia M, Baer M R. FLT3 inhibitors in acute myeloid leukemia: current status and future directions. Molecular cancer therapeutics, 2017, 16(6): 991-1001.
El Fakih R, et al. Targeting FLT3 mutations in acute myeloid leukemia. Cells, 2018, 7(1): 4.
Daver N, et al. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia, 2019, 33(2): 299-312.
Short N J, et al. Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia. Therapeutic advances in hematology, 2019, 10: 2040620719827310.
Wu M, Li C, Zhu X. FLT3 inhibitors in acute myeloid leukemia. Journal of hematology & oncology, 2018, 11(1): 1-11.

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