Abstract
FLT3-ITD and FLT3-TKD mutations were observed in approximately 20 and 10% of acute myeloid leukemia (AML) cases, respectively. FLT3 inhibitors such as midostaurin, gilteritinib and quizartinib show excellent response rates in patients with FLT3-mutated AML, but its duration of response may not be sufficient yet. The majority of cases gain secondary resistance either by on-target and off-target abnormalities. On-target mutations (i.e., FLT3-TKD) such as D835Y keep the TK domain in its active form, abrogating pharmacodynamics of type II FLT3 inhibitors (e.g., midostaurin and quizartinib). Second generation type I inhibitors such as gilteritinib are consistently active against FLT3-TKD as well as FLT3-ITD. However, a “gatekeeper” mutation F691L shows universal resistance to all currently available FLT3 inhibitors. Off-target abnormalities are consisted with a variety of somatic mutations such as NRAS, AXL and PIM1 that bypass or reinforce FLT3 signaling. Off-target mutations can occur just in the primary FLT3-mutated clone or be gained by the evolution of other clones. A small number of cases show primary resistance by an FL-dependent, FGF2-dependent, and stromal CYP3A4-mediated manner. To overcome these mechanisms, the development of novel agents such as covalently-coupling FLT3 inhibitor FF-10101 and the investigation of combination therapy with different class agents are now ongoing. Along with novel agents, gene sequencing may improve clinical approaches by detecting additional targetable mutations and determining individual patterns of clonal evolution.
Highlights
FMS-like tyrosine kinase 3 (FLT3) is classified as a type 3 receptor tyrosine kinase, along withKIT, FMS, and PDGFR [1,2,3]
This paper described the principal mechanisms of resistance to FLT3 inhibition and the current investigations to overcome it
Secondary on-target mutations (i.e., FLT3-TKD) can be managed by choosing type I inhibitors such as gilteritinib that are consistently active against FLT3-TKD as well as
Summary
FMS-like tyrosine kinase 3 (FLT3) is classified as a type 3 receptor tyrosine kinase, along with. Phosphorylated FLT3 activates multiple intracellular signaling pathways involved in the survival, proliferation, and differentiation of hematopoietic stem cells, such as RAS/MAPK, PI3K/Akt/mTOR, and JAK/STAT5 [6,7,8,9]. STAT5 positively regulated Pim-1, which eventually activated mTOR and Mcl-1, which conferred resistance to Akt inhibition in FLT-ITD cell lines [18]. Recent studies suggest that circulating MYBL2, encoded by the cell-cycle checkpoint gene MYBL2, is detected in AML patients with FLT3-ITD mutations and is closely related to mutant FLT3 expression as well as to tumor cell activity [20]. A recent study showed that FLT3-ITD-TKD has the ability to activate STAT5, resulting in Bcl-x and RAD51 upregulation that accounts for drug resistance [25]. We summarize our current understanding of resistance to FLT3 inhibitors and discuss the strategies for overcoming this issue
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