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Open AccessReview

Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance

1
School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia
2
Priority Research Centre for Cancer Research, Innovation & Translation, Faculty of Health & Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
3
John Hunter Children’s Hospital, Faculty of Health and Medicine, University of Newcastle, New Lambton Heights, NSW 2305, Australia
4
Calvary Mater Hospital, Hematology Department, Waratah, NSW 2298, Australia
5
NSW Health Pathology North, John Hunter Hospital, New Lambton Heights, NSW 2305, Australia
*
Author to whom correspondence should be addressed.
These authors contributed equally to the study.
Int. J. Mol. Sci. 2018, 19(10), 3198; https://doi.org/10.3390/ijms19103198
Received: 21 September 2018 / Revised: 10 October 2018 / Accepted: 11 October 2018 / Published: 16 October 2018
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD) present in 30–35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus, encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as a monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance occurs by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain (TKD) at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades; however, little is known about which divergent signaling pathways are controlled by each of the FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways deregulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise of more durable and personalized therapeutic approaches to improve treatments of FLT3 mutant AML. View Full-Text
Keywords: acute myeloid leukemia; FLT3; tyrosine kinase inhibitors; resistance acute myeloid leukemia; FLT3; tyrosine kinase inhibitors; resistance
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Staudt, D.; Murray, H.C.; McLachlan, T.; Alvaro, F.; Enjeti, A.K.; Verrills, N.M.; Dun, M.D. Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance. Int. J. Mol. Sci. 2018, 19, 3198.

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