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)

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 Huang, Dr Xu and Horne, Dr Gillian 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 > School 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