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

Salihanur Darici; Heather G Jørgensen; Xu Huang; Valentina Serafin; Ludovica Antolini; Patrizia Barozzi; Mario Luppi; Fabio Forghieri; Sandra Marmiroli; Manuela Zavatti

doi:10.1016/j.jbior.2023.100974

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

Adv Biol Regul. 2023 Aug:89:100974. doi: 10.1016/j.jbior.2023.100974. Epub 2023 May 23.

Authors

Affiliations

¹ Cellular Signaling Unit, Section of Human Morphology, Department of Biomedical, Metabolic and Neural Sciences, Largo del Pozzo 71, University of Modena and Reggio Emilia, Modena, 41125, Italy; Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK.
² Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK.
³ Department of Surgery Oncology and Gastroenterology Oncology and Immunology Section University of Padova, Italy.
⁴ Cellular Signaling Unit, Section of Human Morphology, Department of Biomedical, Metabolic and Neural Sciences, Largo del Pozzo 71, University of Modena and Reggio Emilia, Modena, 41125, Italy.
⁵ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria Di Modena, Via del Pozzo 71, 41124, Modena, Italy.
⁶ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria Di Modena, Via del Pozzo 71, 41124, Modena, Italy. Electronic address: mario.luppi@unimore.it.
⁷ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria Di Modena, Via del Pozzo 71, 41124, Modena, Italy. Electronic address: fabio.forghieri@unimore.it.
⁸ Cellular Signaling Unit, Section of Human Morphology, Department of Biomedical, Metabolic and Neural Sciences, Largo del Pozzo 71, University of Modena and Reggio Emilia, Modena, 41125, Italy. Electronic address: sandra.marmiroli@unimore.it.

PMID: 37245251
DOI: 10.1016/j.jbior.2023.100974

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.

Keywords: Acute myeloid leukemia (AML); BAY-806946; Combination therapy; FLT3-ITD; PI3K/AKT/mTOR; Quizartinib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzothiazoles / pharmacology
Benzothiazoles / therapeutic use
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / pathology
Mutation
Phosphatidylinositol 3-Kinases* / genetics
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / therapeutic use
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / therapeutic use

Substances

quizartinib
Phosphatidylinositol 3-Kinases
Benzothiazoles
Protein-Tyrosine Kinases
fms-Like Tyrosine Kinase 3
Protein Kinase Inhibitors
FLT3 protein, human