Tyrosine kinase inhibitors targeting FLT3 in the treatment of acute myeloid leukemia

Chen, Yun; Pan, Yihang; Guo, Yao; Zhao, Wanke; Ho, Wan‐Ting; Wang, Jianlong; Xu, Mingjiang; Yang, Feng Chun; Zhao, Zhizhuang Joe

doi:10.21037/sci.2017.05.04

Cited by 31 publications

(23 citation statements)

References 97 publications

(92 reference statements)

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“…The oncogenic potential of 32D cells transfected with FLT3 ITD or FLT3 wt has already been described in a syngeneic setting elsewhere ( 45 ). It is important to note that wild-type FLT3 is regularly expressed on CD34 + hematopoietic stem cells and plays a role in the development of different immune cells (e.g., NK cells, dendritic cells, B cells) [reviewed in ( 66 )]. For co-transplantation experiments, 32D-FLT3 ITD cells were administered together with the allogeneic hematopoietic graft of CD4/DR3 mice, which was shortly pre-incubated with MAX.16H5 IgG 1 before transplantation in C3H/HeN mice as previously described ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia

et al. 2018

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Despite the constant development of innovative therapeutic options for hematological malignancies, the gold-standard therapy regimen for curative treatment often includes allogeneic hematopoietic stem cell transplantation (HSCT). The graft-vs.-leukemia effect (GVL) is one of the main therapeutic goals that arises from HSCT. On the other hand, graft-vs.-host disease (GVHD) is still one of the main and most serious complications following allogeneic HSCT. In acute myeloid leukemia (AML), HSCT together with high-dose chemotherapy is used as a treatment option. An aggressive progression of the disease, a decreased response to treatment, and a poor prognosis are connected to internal tandem duplication (ITD) mutations in the Fms like tyrosine kinase 3 (FLT3) gene, which affects around 30% of AML patients. In this study, C3H/HeN mice received an allogeneic graft together with 32D-FLT3ITD AML cells to induce acute GVHD and GVL. It was examined if pre-incubation of the graft with the anti-human cluster of differentiation (CD) 4 antibody MAX.16H5 IgG1 prevented the development of GVHD and whether the graft function was impaired. Animals receiving grafts pre-incubated with the antibody together with FLT3ITD AML cells survived significantly longer than mice receiving untreated grafts. The observed prolonged survival due to MAX.16H5 incubation of immune cell grafts prior to transplantation may allow an extended application of additional targeted strategies in the treatment of AML.

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Section: Discussionmentioning

confidence: 99%

Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia

et al. 2018

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“…These mutations are in the activation loop of the enzyme and are able to induce an active conformation change [327,328]. Physiologically, the function of FLT3 is to promote survival and proliferation which is accomplished by activating several parallel pathways (Figure 2A) [329]. Several anti-FLT3 drugs have been developed for the treatment of AML patients [329,330].…”

Section: Fms-like Tyrosine Kinase 3 (Flt3)mentioning

confidence: 99%

“…Physiologically, the function of FLT3 is to promote survival and proliferation which is accomplished by activating several parallel pathways (Figure 2A) [329]. Several anti-FLT3 drugs have been developed for the treatment of AML patients [329,330]. Here we only discuss resistant mutations to sorafenib, quizartinib, and sunitinib in AML patients.…”

Section: Fms-like Tyrosine Kinase 3 (Flt3)mentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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“…The most common (and prognostically most relevant) type of FLT3 mutation is the FLT3 ‐ITD (ITD – internal tandem duplication), but mutations can also affect the tyrosine kinase domain (TKD) that is, FLT3 ‐TKD. Both result in a constitutively activated FLT3 signaling pathway . Alterations of the KMT2A ( MLL ) gene include a duplication of part of the gene, the so‐called KMT2A ( MLL ) partial tandem duplication ( MLL ‐PTD) .…”

Section: Biomarkers Of Amlmentioning

confidence: 99%

Measurable residual disease testing for personalized treatment of acute myeloid leukemia

Ehinger

Pettersson

2019

APMIS

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This review summarizes – with the practicing hematologist in mind – the methods used to determine measurable residual disease (MRD) in everyday practice with some future perspectives, and the current knowledge about the prognostic impact of MRD on outcome in acute myeloid leukemia (AML), excluding acute promyelocytic leukemia. Possible implications for choice of MRD method, timing of MRD monitoring, and guidance of therapy are discussed in general and in some detail for certain types of leukemia with specific molecular markers to monitor, including core binding factor (CBF)‐leukemias and NPM1‐mutated leukemias.

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Tyrosine kinase inhibitors targeting FLT3 in the treatment of acute myeloid leukemia

Cited by 31 publications

References 97 publications

Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia

Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Measurable residual disease testing for personalized treatment of acute myeloid leukemia

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