Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain

Heidel, Florian H.; Solem, Fian K.; Breitenbuecher, Frank; Lipka, Daniel B.; Kasper, Stefan; Thiede, Melanie; Brandts, Christian; Serve, Hubert; Roesel, Johannes; Giles, Francis J.; Feldman, Eric J.; Ehninger, Gerhard; Schiller, Gary J.; Nimer, Stephen D.; Stone, Richard; Wang, Yanfeng; Kindler, Thomas; Cohen, Pamela S.; Huber, Christoph; Fischer, Thomas

doi:10.1182/blood-2005-06-2469

Cited by 252 publications

(234 citation statements)

References 28 publications

Supporting

Mentioning

225

Contrasting

Unclassified

Order By: Relevance

“…All cells were maintained in RPMI1640 medium, supplemented with 10% heat inactivated FCS. Parental Ba/F3 cells were cultured in RPMI1640 containing 10% FCS and 10% WEHI-conditioned medium as a source of IL-3 as described (Heidel et al, 2006). Ba/F3-p185 cells retrovirally infected with pLMP vector encoding for non-silencing (control) or PLC-g1-targeting shRNA were Figure 7 Bcr-Abl-induced leukemogenesis is impaired by PLC-g1 knockdown.…”

Section: Cell Linesmentioning

confidence: 99%

See 1 more Smart Citation

Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway

Markova¹,

Albers

Breitenbuecher

et al. 2009

Oncogene

View full text Add to dashboard Cite

Section: Cell Linesmentioning

confidence: 99%

“…The percentage of apoptotic cells was determined by measurement of the fraction with sub-G1 DNA content upon propidium iodide incorporation as described earlier (Kindler et al, 2003;Heidel et al, 2006). Briefly, 4 Â 10 4 cells were treated with various inhibitors for 24 or 48 h, collected and washed with PBS.…”

Section: Antibodiesmentioning

confidence: 99%

Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway

Markova¹,

Albers

Breitenbuecher

et al. 2009

Oncogene

View full text Add to dashboard Cite

“…A recent study suggests that a combination of FLT3 with JAK inhibitors may overcome these resistance mechanisms (62). In addition, incomplete elimination of LSCs will lead to the acquisition of secondary resistance mutations (47), for example, different studies reported the emergence of secondary FLT3 TK domain point mutations in response to FLT3 inhibitor therapy (69,70). Remarkably, in our study, even after exposure of AML mice to Debio 0617B for more up to 130 days, no resistant clones to Debio 0617B could be detected.…”

Section: Discussionmentioning

confidence: 99%

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

Murone

Radpour

Attinger

et al. 2017

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34þ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34 þ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses.

show abstract

“…Specifically, FLT3-ITD-expressing cells resistant to PKC412 only showed mutations within tyrosine kinase domain 1 at residue N676 (von Bubnoff et al, 2009), which has previously been identified in a PKC412-resistant AML patient as the sole cause of drug resistance in the patient (Heidel et al, 2006). FLT3-ITD-expressing cells resistant to SU5614 were characterized mainly by mutations in tyrosine kinase domain 2, predominantly in the D835 residue (von Bubnoff et al, 2009), and FLT3-ITDexpressing cells resistant to sorafenib were unique to sorafenib in their resistance mechanisms, and included the F691L mutation in tyrosine kinase domain 1 and mutations in the Y842 residue in tyrosine kinase domain 2 (von Bubnoff et al, 2009).…”

Section: Flt3 Mutations That Interfere With Drug Bindingmentioning

confidence: 94%

“…For example, resistance to PKC412 in patients has been attributed to preexisting or acquired mutations in the kinase domain of FLT3 (Heidel et al, 2006). This is reminiscent of the most frequent mechanism of resistance to the ABL inhibitor, imatinib: point mutations in the BCR-ABL gene.…”

Section: Flt3 Mutations That Interfere With Drug Bindingmentioning

confidence: 99%

Drug resistance in mutant FLT3-positive AML

et al. 2010

View full text Add to dashboard Cite

Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

show abstract

Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain

Cited by 252 publications

References 28 publications

Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway

Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

Drug resistance in mutant FLT3-positive AML

Contact Info

Product

Resources

About