FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia

Abstract

Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene is a gain-of-function mutation common in acute myeloid leukaemia (AML). It is associated with inferior prognosis and response to chemotherapy. Single base mutations at the FLT3 tyrosine kinase domain (TKD) also leads to a gain of function, although its prognostic significance is less well defined because of its rarity. The clinical benefits of FLT3 inhibition are generally limited to AML with FLT3-ITD. However, responses are transient and leukaemia progression invariably occurs. There is compelling evidence that leukaemia clones carrying both ITD and TKD mutations appear when resistance to FLT3 inhibitors occurs. Interestingly, the emergence of double ITD and TKD mutants can be recapitulated in vitro when FLT3-ITD+ leukaemia cell lines are treated with mutagens and FLT3 inhibitors. Furthermore, murine xenotransplantation models also suggest that, in some cases, the FTL3-ITD and TKD double mutants actually exist in minute amounts before treatment with FLT3 inhibitors, expand under the selection pressure of FLT3 inhibition and become the predominant resistant clone(s) during the drug-refractory phase. On the basis of this model of clonal evolution, a multipronged strategy using more potent FLT3 inhibitors, and a combinatorial approach targeting both FLT3-dependent and FLT3-independent pathways, will be needed to improve outcome.

Identification of a germline F692L drug resistance variant in cis with Flt3-internal tandem duplication in knock-in mice

“…[4][5][6] Herein we report the identification of the germline variant F692L in cis with the Flt3-ITD allele of the widely studied Flt3 tm1Dgg mouse. 4 As this variant is analogous to the human FLT3 F691L "gatekeeper" mutation 3 we investigated this finding further. We found that primary AML cells from Npm1cA; Flt3 tm1Dgg double-mutant mice are resistant to sorafenib and quizartinib (AC220), but sensitive to ponatinib.…”

“…3 Our understanding of the molecular consequences of these mutations has benefited from studies of bespoke mouse models. [4][5][6] Herein we report the identification of the germline variant F692L in cis with the Flt3-ITD allele of the widely studied Flt3 tm1Dgg mouse.…”

“…As the murine F692L variant is equivalent to the human F691L gatekeeper mutation, which confers AML resistance to multiple FLT3 tyrosine kinase inhibitors, 3,15 we proceeded to test whether this was also true for the murine variant. To do this we cultured AML cells from two independent Npm1 cA/+ ; Flt3…”

Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition

“…However, the nature of certain genes mutated in AML suggests strategies for treating patients with molecularly targeted agents. For example, internal tandem duplication (ITD) mutations in Flt3 lead to constitutive activation of its tyrosine kinase activity, and drugs targeting these mutations are in clinical trials (Stirewalt and Radich 2003;Leung et al 2013). Similarly, MEK inhibitors, which interfere with RAS effector mechanisms, show efficacy in certain preclinical models (Lauchle et al 2009).…”

Characterization of gene mutations and copy number changes in acute myeloid leukemia using a rapid target enrichment protocol

“…Additionally, gene mutations may serve as therapeutic targets as shown for example by the clinical efficacy of the tyrosine kinase inhibitor dasatinib for AML with c-KIT mutations, 13,14 and by therapies targeting FLT3-ITD. 15 Next generation sequencing (NGS) technologies introduced rapid sequencing of entire human genomes. 16 AML with normal karyotype was the first cancer whose genome was fully sequenced, 17 and the spectrum of its genomic alterations has since been characterized in hundreds of patients.…”