Multi-target Inhibition of FMS-like Tyrosine Kinase 3 for Patients with Acute Myeloid Leukemia
Introduction. Acute myeloid leukemia (AML) is a malignant hematological cancer of myeloid precursors. The FMS-like tyrosine kinase 3 (FLT3) gene on chromosome 13q12 has been observed to be mutated in roughly 30% of AML cases.1 The FLT3 receptor is involved in cell signaling pathways that oversee gene transcription and cell proliferation, and mutations in the FLT3 gene frequently result in overexpression and subsequent malignant proliferation of myeloid cells.1 The most common mutation of the FLT3 gene is an internal tandem duplication (FLT3-ITD), which disrupts many intracellular pathways such as JAK/STAT, RAS/MAPK, and PI3K/AKT through irreversible autophosphorylation of the kinase receptor.2 Current FLT3 inhibitor drugs like midostaurin have extremely short-term effectiveness in producing therapeutic effects; many patients experience relatively rapid rates of relapse after initial treatment, after which the cancer becomes resistant to FLT3 inhibitors.2,3 Methods. Numerous regulatory pathways may contribute to methods of resistance against FLT3 inhibitor drugs. It was observed through gene knockout studies that protein arginine methyltransferase 1 (PRMT1) is highly expressed in FLT3-ITD cell lines.4 In a separate study, the therapeutic potential of combining first generation FLT3 inhibitors with B-cell lymphoma (Bcl-2) inhibitors was tested using FLT3-ITD cells derived from AML patients.3 The timing of delivery of these drug combinations may also be affected by stem cell transplantation. Clinical studies demonstrated that midostaurin-treated patients who received a stem cell transplant while in complete remission fared better than those who received a transplant outside of complete remission.5 Results. PRMT1 is highly expressed in AML patients, where it methylates FLT3-ITD and contributes to its upregulated activity. Furthermore, FLT3 inhibitors had greater inhibitory effects on cancerous cells when combined with Bcl-2 inhibitors. Conclusions. Developing a viable PRMT1 inhibitor for patients with AML FLT3-ITD may be a potent tool for co-administering with venetoclax and midostaurin. The therapeutic benefits of these drugs may be enhanced after optimized timing of stem cell transplantation. Gilteritinib, a second generation FLT3-ITD inhibitor, may be more effective than midostaurin in optimizing treatment of AML. It is currently undergoing clinical trials to test its effectiveness with stem cell transplantation.3 Future research is necessary to optimize the delivery of FLT3 inhibitors in combination with these therapeutic strategies in order to improve the prognosis of AML patients.
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- Ma J, Zhao S, Qiao X, et al. Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia. Clin Cancer Res. 2019;25(22):6815-6826. https://doi.org/10.1158/1078-0432.CCR-19-0832
- He X, Zhu Y, Lin YC, et al. PRMT1-mediated FLT3 arginine methylation promotes maintenance of FLT3-ITD+ acute myeloid leukemia. Blood. 2019;134(6):548-560. https://doi.org/10.1182/blood.2019001282
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