Pharmacological impact of FLT3 mutations on receptor activity and responsiveness to tyrosine kinase inhibitors

Marensi, V., Keeshan, K. R. and MacEwan, D. J. (2021) Pharmacological impact of FLT3 mutations on receptor activity and responsiveness to tyrosine kinase inhibitors. Biochemical Pharmacology, 183, 114348. (doi: 10.1016/j.bcp.2020.114348) (PMID:33242449)

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Acute myelogenous leukaemia (AML) is an aggressive blood cancer characterized by the rapid proliferation of immature myeloid blast cells, resulting in a high mortality rate. The 5-year overall survival rate for AML patients is approximately 25%. Circa 35% of all patients carry a mutation in the FLT3 gene which have a poor prognosis. Targeting FLT3 receptor tyrosine kinase has become a treatment strategy in AML patients possessing FLT3 mutations. The most common mutations are internal tandem duplications (ITD) within exon 14 and a single nucleotide polymorphism (SNP) that leads to a point mutation in the D835 of the tyrosine kinase domain (TKD). Variations in the ITD sequence and the occurrence of other point mutations that lead to ligand-independent FLT3 receptor activation create difficulties in developing personalized therapeutic strategies to overcome observed mutation-driven drug resistance. Midostaurin and quizartinib are tyrosine kinase inhibitors (TKIs) with inhibitory efficacy against FLT3-ITD, but exhibit limited clinical impact. In this review, we focus on the structural aspects of the FLT3 receptor and correlate those mutations with receptor activation and the consequences for molecular and clinical responsiveness towards therapies targeting FLT3-ITD positive AML.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Keeshan, Dr Karen
Authors: Marensi, V., Keeshan, K. R., and MacEwan, D. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Biochemical Pharmacology
ISSN (Online):1873-2968
Published Online:23 November 2020
Copyright Holders:Copyright © 2020 Elsevier Inc.
First Published:First published in Biochemical Pharmacology 183:114348
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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