Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis

Smith, Catherine C.; Paguirigan, Amy L.; Jeschke, Grace R.; Lin, Kai; Massi, Evan; Tarver, Theodore C.; Chin, Chen-Shan; Asthana, Saurabh; Olshen, Adam B.; Travers, Kevin; Wang, Susana; Levis, Mark J.; Perl, Alexander E.; Radich, Jerald P.; Shah, Neil P.

doi:10.1182/blood-2016-04-711820

Cited by 150 publications

(139 citation statements)

References 41 publications

Supporting

Mentioning

133

Contrasting

Order By: Relevance

“…residues. 17 We demonstrated the ability of midostaurin to behave as a relatively high resistance to venetoclax as a single agent as has been previously reported. 39 We generally observed some combinations between midostaurin and standard chemotherapeutic agents to show stronger synergy than others, with comparatively weaker combination effects observed for the simultaneous administration of midostaurin+ Ara-C against both mutant FLT3-and wt FLT3-expressing cells.…”

Section: Discussionsupporting

confidence: 74%

“…This is compared to an overall response rate of second‐generation FLT3 inhibitors as single agents of 40%‐50%; however, duration of response is short and haematologic recovery is incomplete for these inhibitors . Other limitations of second‐generation FLT3 inhibitors include a short (6‐8 hours) half‐life for crenolanib, requiring thrice‐daily dosing, and a lack of activity of quizartinib against FLT3‐TKD mutants such as those occurring at the D835 or F691 residues …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of the multi‐kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia

Weisberg

Meng

Case

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

Recently, several targeted agents have been developed for specific subsets of patients with acute myeloid leukaemia (AML), including midostaurin, the first FDA‐approved FLT3 inhibitor for newly diagnosed patients with FLT3 mutations. However, in the initial Phase I/II clinical trials, some patients without FLT3 mutations had transient responses to midostaurin, suggesting that this multi‐targeted kinase inhibitor might benefit AML patients more broadly. Here, we demonstrate submicromolar efficacy of midostaurin in vitro and efficacy in vivo against wild‐type (wt) FLT3‐expressing AML cell lines and primary cells, and we compare its effectiveness with that of other FLT3 inhibitors currently in clinical trials. Midostaurin was found to synergize with standard chemotherapeutic drugs and some targeted agents against AML cells without mutations in FLT3. The mechanism may involve, in part, the unique kinase profile of midostaurin that includes proteins implicated in AML transformation, such as SYK or KIT, or inhibition of ERK pathway or proviability signalling. Our findings support further investigation of midostaurin as a chemosensitizing agent in AML patients without FLT3 mutations.

show abstract

Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Effects of the multi‐kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia

Weisberg

Meng

Case

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…FLT3 inhibitors have been shown to be effective in FLT3/ITD AML (Assi & Ravandi, 2018). However, tyrosine kinase domain (TKD) mutations in FLT3 confer drug resistance and are an important cause of treatment failure (Man et al, 2012;Smith et al, 2017). Identifying new pathogenetic signals in FLT3/ITD AML may result in novel therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Follistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia

Yang

Man

et al. 2020

EMBO Mol Med

View full text Add to dashboard Cite

Internal tandem duplication of Fms‐like tyrosine kinase 3 (FLT3/ITD) occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor response to conventional treatment and adverse outcome. Here, we reported that human FLT3/ITD expression led to axis duplication and dorsalization in about 50% of zebrafish embryos. The morphologic phenotype was accompanied by ectopic expression of a morphogen follistatin (fst) during early embryonic development. Increase in fst expression also occurred in adult FLT3/ITD‐transgenic zebrafish, Flt3/ITD knock‐in mice, and human FLT3/ITD AML cells. Overexpression of human FST317 and FST344 isoforms enhanced clonogenicity and leukemia engraftment in xenotransplantation model via RET, IL2RA, and CCL5 upregulation. Specific targeting of FST by shRNA, CRISPR/Cas9, or antisense oligo inhibited leukemic growth in vitro and in vivo. Importantly, serum FST positively correlated with leukemia engraftment in FLT3/ITD AML patient‐derived xenograft mice and leukemia blast percentage in primary AML patients. In FLT3/ITD AML patients treated with FLT3 inhibitor quizartinib, serum FST levels correlated with clinical response. These observations supported FST as a novel therapeutic target and biomarker in FLT3/ITD AML.

show abstract

“…This is an attractive venture because it will yield information – as the word implies – from single leukaemic cells out of a total population of malignant cells (Gawad et al , ). That single cell studies can still lead to novel observations in AML is evidenced by a recent report, which revealed a surprising heterogeneity in the response to a FLT3 tyrosine kinase inhibitor at the single cell level (Smith et al , ). This contrasts to bulk analyses, which depends on some computational generalisations in order to establish mutational or coarse clonal frequencies (Hansen et al , ).…”

Section: The Present Toolbox For Aml Lsc Characterisationmentioning

confidence: 99%

The concept of leukaemic stem cells in acute myeloid leukaemia 25 years on: hitting a moving target

et al. 2019

View full text Add to dashboard Cite

Summary The concept of leukaemic stem cells (LSCs) was experimentally suggested 25 years ago through seminal data from John Dick's group, who showed that a small fraction of cells from acute myeloid leukaemia (AML) patients were able to be adoptively transferred into immunodeficient mice. The initial estimation of the frequency was 1:250 000 leukaemic cells, clearly indicating the difficulties ahead in translating knowledge on LSCs to the clinical setting. However, the field has steadily grown in interest, expanse and importance, concomitantly with the realisation of the molecular background for AML culminating in the sequencing of hundreds of AML genomes. The literature is now ripe with contributions describing how different molecular aberrations are more or less specific for LSCs, as well as reports showing selectivity in targeting LSCs in comparison to normal haematopoietic stem and progenitor cells. However, we argue here that these important data have not yet been fully realised within the clinical setting. In this clinically focused review, we outline the difficulties in identifying and defining LSCs at the individual patient level, with special emphasis on intraclonal heterogeneity. In addition, we suggest areas of future focus in order to realise the concept as real‐time benefit for AML patients.

show abstract

Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis

Cited by 150 publications

References 41 publications

Effects of the multi‐kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia

Effects of the multi‐kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia

Follistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia

The concept of leukaemic stem cells in acute myeloid leukaemia 25 years on: hitting a moving target

Contact Info

Product

Resources

About