Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia

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.

A Novel FLT3 Y842D Mutation Carriers a Potentially Highly Sensitivity to Midostaurin? Case Report and Literature Review

“…Mutant FLT3 contained two kinds of mutation forms, internal tandem duplication (ITD) in juxtamembrane domain and point mutation within the activation loop of tyrosine kinase domain (TKD) [2] . FLT3 mutation occurred in 30% of de novo AML patients and accounted for the most predominant mutation type in AML [1] .…”

“…In combination with standard 3 + 7 regimen, molecular targeted agents were supposed to improve remission rate of induction therapy effectively and provide more opportunities for subsequent HSCT [14] . Mutant FLT3 contained two kinds of mutation forms, internal tandem duplication (ITD) in juxtamembrane domain and point mutation within the activation loop of tyrosine kinase domain (TKD) [2] . FLT3 mutation occurred in 30% of de novo AML patients and accounted for the most predominant mutation type in AML [1] .…”

“…Certain alteration of this protein can constitutively active receptor tyrosine kinase causing uncontrolled proliferation, reduced apoptosis, and malignant transformation of myeloid cells [1] . Thus, mutant FLT3 is well known as a promising target for molecular therapy in acute myeloid leukemia (AML) [1,2] . FLT3 mutation occurred in 30% of de novo AML, with internal tandem duplication (FLT3-ITD) in juxtamembrane domain observed in 75% of mutant patients and point mutation within the activation loop of tyrosine kinase domain (FLT3-TKD) in the rest of 25% patients [3] .…”

Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition

“…Improved therapies are likewise necessary for poor-prognosis acute myeloid leukemia (AML) patients with internal tandem duplication in the FMS-like tyrosine kinase (FLT3-ITD). Such cells are susceptible to specific TKi but become drug-refractory due to secondary, therapy-associated tyrosine kinase mutations in the FLT3 kinase domain (FLT3-TKD) [16][17][18].…”

A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia

“…However, clinical responses to these drugs are transient because of high rates of relapse and drug resistance after treatment, which contributes to disease progression and poor overall survival [ 4 , 5 ]. One particular mechanism for resistance involves acquired additional mutations in the TKD and a “gatekeeper” mutation (F691L) is resistant to most currently available FLT3 inhibitors [ 6 , 7 ]. Therefore, finding effective compounds to overcome the drug resistance caused by F691L and other mutations is an urgent problem.…”