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<b>Abstract</b>— <p>Investigating the mechanisms of resistance of acute myeloid leukemia (AML) cells to anticancer therapy, including targeted drugs such as the FLT3 inhibitor quizartinib, remains highly relevant in modern molecular oncology. In this work, we explored the mechanisms underlying quizartinib resistance in macrophage-like THP-1ad cells. We demonstrated that resistance is associated with downregulation of the expression of the FLT3 receptor due to suppressed FLT3 gene transcriptional activity, while key downstream signaling pathways (STAT5, PI3K/AKT, ERK) remain functionally active. The findings indicate that resistance to FLT3 inhibitors in AML cells may develop independently of classical mutational mechanisms, but rather through alternative activation of signaling cascades. These results expand current understanding of resistance mechanisms in AML and support the rationale for targeting signaling pathways downstream of FLT3 as a promising strategy to overcome resistance in tumor cells refractory to FLT3 inhibitors.</p>

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Activation of FLT3-Associated Signaling Pathways in Quizartinib-Resistant Macrophage-Like Cells of Acute Myeloid Leukemia

  • 期刊论文

  • 发表日期：

    2026年2月2日

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  • Ya. V. Lomovskaya,
  • M. I. Kobyakova,
  • K. S. Krasnov,
  • A. I. Lomovsky,
  • E. I. Meshcheriakova,
  • R. S. Fadeev

摘要

Abstract—

Investigating the mechanisms of resistance of acute myeloid leukemia (AML) cells to anticancer therapy, including targeted drugs such as the FLT3 inhibitor quizartinib, remains highly relevant in modern molecular oncology. In this work, we explored the mechanisms underlying quizartinib resistance in macrophage-like THP-1ad cells. We demonstrated that resistance is associated with downregulation of the expression of the FLT3 receptor due to suppressed FLT3 gene transcriptional activity, while key downstream signaling pathways (STAT5, PI3K/AKT, ERK) remain functionally active. The findings indicate that resistance to FLT3 inhibitors in AML cells may develop independently of classical mutational mechanisms, but rather through alternative activation of signaling cascades. These results expand current understanding of resistance mechanisms in AML and support the rationale for targeting signaling pathways downstream of FLT3 as a promising strategy to overcome resistance in tumor cells refractory to FLT3 inhibitors.