Developments and challenges of FLT3 inhibitors in acute myeloid leukemia

by Selleckchem | Oct 31 2023

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.

Comments:

FLT3 mutations play a significant role in acute myeloid leukemia (AML), with approximately one-third of newly diagnosed AML patients having these genetic alterations. The abnormal signaling of the FLT3 receptor has important implications for the biology and clinical management of AML. In recent years, targeting FLT3 has become a crucial component of treatment regimens for AML patients with FLT3-ITD/TKD mutations, leading to significant improvements in survival rates.

The advent of next-generation sequencing (NGS) technology has allowed for the identification of various non-canonical FLT3 mutations, including point mutations and small insertions/deletions. Some of these mutations may affect downstream phosphorylation and sensitivity to FLT3 inhibitors, although their correlation with clinical outcomes is not yet fully understood.

While progress has been made in the development of FLT3-targeted therapies, the emergence of resistance to FLT3 inhibitors has become a pressing issue. The mechanisms underlying resistance to FLT3 inhibitors can be broadly categorized into primary resistance and secondary resistance. Primary resistance is associated with abnormalities in signaling factors such as FL, CXCL12, and FGF2, while secondary resistance involves on-target mutations and off-target aberrations.

To address this challenge, novel agents like FF-10101 have shown promising potential in overcoming resistance to FLT3 inhibitors. Additionally, multitarget strategies that simultaneously target FLT3 and abnormal signaling factors are actively being developed and have demonstrated promising results in clinical settings.

Overall, the understanding of FLT3 mutations and the development of targeted therapies have significantly improved outcomes for AML patients with FLT3-ITD/TKD mutations. Ongoing research and clinical trials are focused on elucidating the impact of non-canonical FLT3 mutations and developing effective strategies to overcome resistance to FLT3 inhibitors.