Synergistic cytotoxicity of dual PI3K/mTOR and FLT3 inhibition in FLT3-ITD AML cells

Darici, S. et al. (2021) Synergistic cytotoxicity of dual PI3K/mTOR and FLT3 inhibition in FLT3-ITD AML cells. Advances in Biological Regulation, 82, 100830. (doi: 10.1016/j.jbior.2021.100830) (PMID:34555701)

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Abstract

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy, characterized by a heterogeneous genetic landscape and complex clonal evolution, with poor outcomes. Mutation at the internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic alterations in AML, associated with high relapse rates and poor survival due to the constitutive activation of the FLT3 receptor tyrosine kinase and its downstream effectors, such as PI3K signaling. Thus, aberrantly activated FLT3-kinase is regarded as an attractive target for therapy for this AML subtype, and a number of small molecule inhibitors of this kinase have been identified, some of which are approved for clinical practice. Nevertheless, acquired resistance to these molecules is often observed, leading to severe clinical outcomes. Therapeutic strategies to tackle resistance include combining FLT3 inhibitors with other antileukemic agents. Here, we report on the preclinical activity of the combination of the FLT3 inhibitor quizartinib with the dual PI3K/mTOR inhibitor PF-04691502 in FLT3-ITD cells. Briefly, we show that the association of these two molecules displays synergistic cytotoxicity in vitro in FLT3-ITD AML cells, triggering 90% cell death at nanomolar concentrations after 48 h.

Item Type:Articles
Additional Information:This research was supported by grants from the not-for-profit Associazione Mantovana per la Ricerca sul Cancro (A.Ma.Ri.Ca); V.S has received funding from Fondazione Associazione Italiana per la Ricerca sul Cancro (AIRC) under MFAG 2018 - ID. 21771.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jorgensen, Dr Heather and Horne, Dr Gillian and Huang, Dr Xu and Darici, Ms Salihanur
Authors: Darici, S., Zavatti, M., Braglia, L., Accordi, B., Serafin, V., Horne, G. A., Manzoli, L., Palumbo, C., Huang, X., Jørgensen, H. G., and Marmiroli, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Advances in Biological Regulation
Publisher:Elsevier
ISSN:2212-4926
ISSN (Online):2212-4934
Published Online:17 September 2021
Copyright Holders:Copyright © 2021 Elsevier Ltd
First Published:First published in Advances in Biological Regulation
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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