Related Experiment Video
Updated: Aug 27, 2025
Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
Published on: June 6, 2025
Developments and challenges of FLT3 inhibitors in acute myeloid leukemia
Shuai-Shuai Ge1,2, Song-Bai Liu3, Sheng-Li Xue1,2
1National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Abstract:
FLT3 mutations are one of the most common genetic alterations in acute myeloid leukemia (AML) and are identified in approximately one-third of newly diagnosed patients. Aberrant FLT3 receptor signaling has important implications for the biology and clinical management of AML. In recent years, targeting FLT3 has been a part of every course of treatment in FLT3-ITD/TKD-mutated AML and contributes to substantially prolonged survival. At the same time, wide application of next-generation sequencing (NGS) technology has revealed a series of non-canonical FLT3 mutations, including point mutations and small insertions/deletions. Some of these mutations may be able to influence downstream phosphorylation and sensitivity to FLT3 inhibitors, while the correlation with clinical outcomes remains unclear. Exploration of FLT3-targeted therapy has made substantial progress, but resistance to FLT3 inhibitors has become a pressing issue. The mechanisms underlying FLT3 inhibitor tolerance can be roughly divided into primary resistance and secondary resistance. Primary resistance is related to abnormalities in signaling factors, such as FL, CXCL12, and FGF2, and secondary resistance mainly involves on-target mutations and off-target aberrations. To overcome this problem, novel agents such as FF-10101 have shown promising potential. Multitarget strategies directed at FLT3 and anomalous signaling factors simultaneously are in active clinical development and show promising results.
Insights
FLT3 mutations are common in acute myeloid leukemia (AML). Targeting FLT3 improves survival, but resistance is a challenge. Novel agents and multitarget strategies show promise for overcoming resistance in AML treatment.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent in acute myeloid leukemia (AML), affecting approximately one-third of diagnoses.
- Aberrant FLT3 signaling is crucial for AML biology and treatment strategies.
- FLT3-targeted therapies have significantly improved survival in FLT3-mutated AML.
Purpose of the Study:
- To review the role of FLT3 mutations in AML.
- To discuss the challenges and mechanisms of resistance to FLT3 inhibitors.
- To highlight emerging therapeutic strategies for overcoming resistance.
Main Methods:
- Review of current literature on FLT3 mutations in AML.
- Analysis of resistance mechanisms to FLT3 inhibitors.
- Evaluation of novel therapeutic agents and strategies.
Main Results:
- Next-generation sequencing reveals non-canonical FLT3 mutations impacting inhibitor sensitivity.
- Resistance to FLT3 inhibitors arises from primary (signaling factors) and secondary (on-target/off-target aberrations) mechanisms.
- Novel agents like FF-10101 and multitarget strategies demonstrate potential in overcoming resistance.
Conclusions:
- FLT3-targeted therapy is a cornerstone in managing FLT3-mutated AML.
- Understanding resistance mechanisms is critical for developing effective treatment protocols.
- Emerging therapies offer new hope for patients with refractory or resistant AML.
