FLT3 mutants bind TKIs

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R-HSA-9702509
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Homo sapiens
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Aberrant signaling by activated forms of FLT3 can be inhibited by tyrosine kinase inhibitors (TKIs). FLT3 receptors are class III receptor tyrosine kinase receptors, also known as dual-switch. Dual-switch receptors are activated through a series of phosphorylation and conformational changes that move the receptor from the inactive form to the fully activated form. Type II TKIs bind to the inactive form of the receptor at a site adjacent to the ATP-binding cleft, while type I TKIs bind to the active form (reviewed in Klug et al, 2018; Daver et al, 2019).

FLT3 internal tandem duplications (ITDs) are found in ~25-30% of acute myeloid leukemias, and are present at lower frequencies in other cancers (reviewed in Kazi and Roostrand, 2019; Patnaik et al, 2018). These ITDs generally occur in a tyrosine-rich region of exon 14, encoding the juxtamembrane domain region of the protein; at a lower frequency, ITDs are found in the first tyrosine kinase domain (TKD1). In addition to ITDs, a number of point mutations in the juxtamembrane domain have also been identified. Juxtamembrane domain mutations affect an autoinhibitory loop, shifting the equilibrium of the receptor towards the activated state; despite this, however, juxtamembrane domain mutants remain predominantly in the inactive state and as such are susceptible to inhibition by type II TKIs (reviewed in Patnaik et al, 2018; Kazi and Roonstrand et al, 2019).

Activation loop mutations more strongly favor the active conformation of the receptor and are susceptible to inhibition by both type II and type I TKIs. The most prevalent FLT3 mutation, D835Y, promotes the active conformation strongly enough to be resistant to type II TKIs (Patnaik et al, 2017; Klug et al, 2018; Daver et al, 2019).

Literature References
PubMed ID Title Journal Year
30651634 Targeting FLT3 mutations in AML: review of current knowledge and evidence

Daver, N, Schlenk, RF, Russell, NH, Levis, MJ

Leukemia 2019
31066629 FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

Kazi, JU, Rönnstrand, L

Physiol. Rev. 2019
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Klug, LR, Kent, JD, Heinrich, MC

Pharmacol. Ther. 2018
29164965 The importance of FLT3 mutational analysis in acute myeloid leukemia

Patnaik, MM

Leuk. Lymphoma 2018
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cancer 162 malignant tumor, malignant neoplasm, primary cancer
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