Quizartinib resistance mechanism

Quizatinib is an oral, potent fms-like tyrosine kinase3(FLT3 span>) inhibitor, specifically used to treat patients with FLT3-ITD-positive acute myeloid leukemia (AML). However, with the widespread clinical application of quizartinib, its drug resistance problem has gradually emerged. The following is a detailed explanation of the mechanism of resistance to Quizartinib:

1. FLT3Second mutation

Secondary mutation phenomenon: A genomic study of samples from FLT3-ITDpositiveAML patients who relapsed after using quizartinib found that all patients had FLT3-ITD Secondary mutations occurred in the activation loop residue D835 or the gatekeeping residue F691 in span>'s TKD (tyrosine kinase domain). These mutations change the structure of the FLT3 receptor and reduce the affinity of quizartinib to the FLT3 receptor, thus leading to the development of drug resistance.

Polyclonal resistance mechanism: The study also found that some patients developed multiple FLT3-TKD mutations when the disease relapsed, indicating the existence of a polyclonal resistance mechanism. That is, different leukemia cell clones may escape the inhibitory effects of quizartinib through different FLT3 mutations.

2. FLT3Elevated ligand levels

Effect of FLT3ligands: Standard induction chemotherapy may result in increased plasma levels of FLT3ligands. After the FLT3ligand binds to the FLT3 receptor, it will change the conformation of the FLT3 receptor from an inactive state to an active state, thus bypassing the inhibitory effect of quizartinib.

Resistance mechanism: thisFLT3Receptor conformational changes caused by elevated ligand levels provide leukemia cells with a new survival and proliferation pathway, leading to drug resistance.

3. Upregulation of other signaling pathways

Activation of FGF2 and FGFR1: FLT3-ITDpositiveAMLpatients, FGF2 (fibroblast growth factor 2) expression is increased in bone marrow stromal cells. FGF2promotes the development of drug resistance by activating FGFR1 (fibroblast growth factor receptor 1) and the downstream MAPK (mitogen-activated protein kinase) pathway.

RAS/MAPK signaling pathway mutations: Even in the case of FLT3-ITD loss, the resistance mechanism to FLT3 inhibitors may involve mutations in other signaling pathways. For example, mutations in the RAS/MAPK signaling pathway are more common in patients who relapse after treatment with quizartinib. These mutations may compensate for the effects of FLT3 inhibition by activating alternative signaling pathways, thereby leading to drug resistance.

4. Resistance mechanism of combination therapy

Not fully explored: Although the combination therapy of quizartinib and chemotherapy has shown certain efficacy in AML patients, its resistance mechanism has not been fully explored. This may be related to various factors such as interactions between different drugs, individual differences among patients, and the tumor microenvironment.

In summary, the resistance mechanism of quizartinib is a complex process, involving secondary mutations of FLT3, increased levels of FLT3 ligands, upregulation of other signaling pathways, and resistance mechanisms of combination therapy. Understanding these resistance mechanisms is of great significance for optimizing treatment options for AML patients and improving treatment effects.

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References: https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01617-7