Developments and challenges of FLT3 inhibitors in acute myeloid leukemia

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.

A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis

“…Previous targeting of FLT3 initially showed high promise as an effective treatment, but resistance to FLT3 inhibitors is already becoming a pressing issue that would need to be addressed for this to be effective long-term. Current ideas suggest that there are two forms of resistance (primary and secondary) and that these are caused by different underlying mechanisms [108]. One example of a primary resistance causing mechanism is that the upregulation of CXCL12 and FGF2 within the bone marrow microenvironment can shield AML blasts from FLT3 inhibitors [109,110].…”

Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions

“…Stroma-derived cytokines and/or direct contact with stromal cells allows for FLT3-ITDindependent activation of the RAS/MEK/ERK pathway, contributing to the survival of leukemic blasts within the bone marrow despite FLT3 inhibition [ 58 ]. FLT3-ligand, a growth factor produced by bone marrow stromal cells and T-lymphocytes, plays an important role in the homeostasis of hematopoietic progenitor cells [ 59 ]. FL rises when the bone marrow niche is compromised, and its levels are inversely proportional to the fraction of FLT3 mut blasts.…”

“…Wild type (WT)-FLT3 is commonly co-expressed alongside mutated FLT3 on leukemic cells. In the post-induction phase, binding of abundant FL to WT-FLT3 allows for downstream signaling via activation of an RAS/MEK/ERK pathway nourishing and promoting proliferation of remailing FLT3 mut leukemic cells despite FLT3i ( Figure 1 , pathway 1) [ 59 , 62 ].…”

“…The third mechanism makes the FLT3 more active, increasing the speed of downstream reactions and/or increased affinity to its substrate. An example of such activating mutation is M664I, which confers resistance to pexidartinib—Type 2 inhibitor that has activity against FLT3 with F691 mutation ( Figure 1 , pathway 5) [ 1 , 57 , 59 ].…”

“…One such novel combination employs BTKi and FLT3i. BTK inhibition with ibrutinib appears to enhance quizartinib-mediated apoptosis even in FLT3 -ITD/D835Y mutated AML cells [ 30 , 59 ]. Aurora kinase inhibition is also being actively investigated for the treatment of FLT3 mut AML.…”