Effect of Quizartinib on the Resistance of Acute Myeloid Leukemia Cells with FLT3-ITD-Positive and FLT3-ITD-Negative Phenotypes to the TRAIL-Induced Apoptosis

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Margarita I. Kobyakova^1,2,a*, Yana V. Lomovskaya¹, Kirill S. Krasnov^1,2, Irina V. Odinokova¹, Elena I. Meshcheriakova^1,3, Artem M. Ermakov^1,4, Alina S. Didenko⁵, Anatoly S. Senotov¹, Irina S. Fadeeva¹, and Roman S. Fadeev^1,2

¹Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

²Institute of Clinical and Experimental Lymphology, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630060 Novosibirsk, Russia

³Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

⁴Nanoporus, 142200 Serpukhov, Moscow Region, Russia

⁵Faculty of Biotechnology, Lomonosov Moscow State University, 119234 Moscow, Russia

^* To whom correspondence should be addressed.

Received: August 28, 2025; Revised: November 10, 2025; Accepted: November 11, 2025

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Internal tandem duplications in the gene encoding the membrane domain of FLT3 (FLT3-ITD) are the most common genetic alteration and an unfavorable prognostic factor in the patients with acute myeloid leukemia (AML). New-generation FLT3 inhibitors effectively induce cell death in the AML cells with the FLT3-ITD-positive phenotype (FLT3-ITD⁺) and potentially exhibit cytotoxic activity against the AML cells with the FLT3-ITD-negative phenotype (FLT3-ITD⁻), but at higher concentrations. However, potential impact of the new-generation FLT3 inhibitors on the cytotoxic activity of molecular effectors of antitumor immunity – particularly in the context of heterogeneity of the primary clonal composition of AML, which includes both FLT3-ITD⁺ and FLT3-ITD⁻ cells – remains unclear. This study demonstrated that the use of quizartinib, a new-generation FLT3 inhibitor, increased resistance of the FLT3-ITD⁻ AML cells, but not of the FLT3-ITD⁺ AML cells, to the cytotoxic action of the key molecular effector of antitumor immunity, the cytokine Apo2L/TRAIL. This effect was mediated by the changes in the expression of proapoptotic TRAIL receptors, content of the cFLIP protein, and expression of the genes encoding proteins of the IAP and BCL-2 families. Additionally, the quizartinib-induced changes in the intracellular signaling pathways that potentially regulate TRAIL resistance in the AML cells were identified. The identified quizartinib-induced transcriptional changes are of interest not only in the context of combination therapy with TRAIL but also have broader implications for understanding the mechanisms of drug resistance in the AML cells.

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KEY WORDS: acute myeloid leukemia, FLT3, quizartinib, resistance, cytokine Apo2L/TRAIL

DOI: 10.1134/S000629792560276X

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