Improved efficacy of quizartinib in combination therapy with PI3K inhibition in primary FLT3-ITD AML cells

Darici, S., Jørgensen, H. G. , Huang, X. , Serafin, V., Antolini, L., Barozzi, P., Luppi, M., Forghieri, F., Marmiroli, S. and Zavatti, M. (2023) Improved efficacy of quizartinib in combination therapy with PI3K inhibition in primary FLT3-ITD AML cells. Advances in Biological Regulation, 89, 100974. (doi: 10.1016/j.jbior.2023.100974) (PMID:37245251)

Abstract

Acute myeloid leukemia is a heterogeneous hematopoietic malignancy, characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells, with poor outcomes. The internal tandem duplication (ITD) mutation of the Fms-like receptor tyrosine kinase 3 (FLT3) (FLT3-ITD) represents the most common genetic alteration in AML, detected in approximately 30% of AML patients, and is associated with high leukemic burden and poor prognosis. Therefore, this kinase has been regarded as an attractive druggable target for the treatment of FLT3-ITD AML, and selective small molecule inhibitors, such as quizartinib, have been identified and trialled. However, clinical outcomes have been disappointing so far due to poor remission rates, also because of acquired resistance. A strategy to overcome resistance is to combine FLT3 inhibitors with other targeted therapies. In this study, we investigated the preclinical efficacy of the combination of quizartinib with the pan PI3K inhibitor BAY-806946 in FLT3-ITD cell lines and primary cells from AML patients. We show here that BAY-806946 enhanced quizartinib cytotoxicity and, most importantly, that this combination increases the ability of quizartinib to kill CD34 CD38 leukemia stem cells, whilst sparing normal hematopoietic stem cells. Because constitutively active FLT3 receptor tyrosine kinase is known to boost aberrant PI3K signaling, the increased sensitivity of primary cells to the above combination can be the mechanistic results of the disruption of signaling by vertical inhibition.

• Item Type: Articles
• Keywords: FLT3-ITD, combination therapy, quizartinib, BAY-806946, acute myeloid leukemia (AML), PI3K/AKT/mTOR.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jorgensen, Dr Heather and Huang, Dr Xu and Darici, Ms Salihanur
• Authors: Darici, S., Jørgensen, H. G., Huang, X., Serafin, V., Antolini, L., Barozzi, P., Luppi, M., Forghieri, F., Marmiroli, S., and Zavatti, M.
• 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: 23 May 2023
• Copyright Holders: Crown Copyright © 2023
• First Published: First published in Advances in Biological Regulation 89:100974
• Publisher Policy: Reproduced in accordance with the publisher copyright policy