Drug resistance of FLT3 mutants

Stable Identifier
Homo sapiens
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FLT3 is mutated in ~30% of acute myeloid leukemias (AML), with internal tandem duplications (ITDs) representing the majority of these mutations and activating point mutants occurring at lower frequency. FLT3 mutations also occur at lower rates in other cancers (reviewed in Kazi and Roonstrand, 2018; Daver et al, 2019; Larroas-Garcia and Baer, 2017). Mutation of FLT3 has been identified as a driver in progression of AML and in consequence is a promising therapeutic target. A number of first and second generation inhibitors have been demonstrated to have activity against FLT3, but accumulation of secondary mutations leads to the development of resistance. These secondary mutations further shift the equilibrium of the receptor toward the activated state, making even the second-generation type II TKIs less effective. In consequence, considerable effort is devoted to discovery of type II and, in particular, type I TKIs that are active against highly activated FLT3 alleles (reviewed in Daver et al, 2019; Staudt et al, 2018; Lim et al, 2017; Klug et al, 2018).
Literature References
PubMed ID Title Journal Year
31066629 FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

Kazi, JU, Rönnstrand, L

Physiol. Rev. 2019
30651634 Targeting FLT3 mutations in AML: review of current knowledge and evidence

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

Leukemia 2019
28576946 FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

Baer, MR, Larrosa-Garcia, M

Mol. Cancer Ther. 2017
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Heinrich, MC, Kent, JD, Klug, LR

Pharmacol. Ther. 2018
28851395 Molecular targeting in acute myeloid leukemia

Dubielecka, PM, Lim, SH, Raghunathan, VM

J Transl Med 2017
30332834 Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance

Staudt, D, Murray, HC, Alvaro, F, Dun, MD, Enjeti, AK, McLachlan, T, Verrills, NM

Int J Mol Sci 2018
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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