Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML

Zhou, Jianbiao; Bi, Chonglei; Janakakumara, Jasinghe Viraj; Liu, Shaw-Cheng; Chng, Wee‐Joo; Tay, Kian-Ghee; Poon, Lai Fong; Xie, Zhigang; Palaniyandi, Senthilnathan; Yu, Hanry; Glaser, Keith B.; Albert, Daniel H.; Davidsen, Steven K.; Chen, Chien-Shing

doi:10.1182/blood-2008-05-156422

Cited by 141 publications

(161 citation statements)

References 51 publications

Supporting

Mentioning

148

Contrasting

Order By: Relevance

“…Our data extend findings previously obtained using leukemic cell lines with acquired resistance to TKI showing continued STAT5 activation in resistant cells (43,44). Prolonged exposure of leukemic cell lines or AML blasts to TKI opts for cells that are FLT3 independent, leading to pharmacologic resistance (35,43,44).…”

Section: Discussionsupporting

confidence: 76%

See 1 more Smart Citation

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

et al. 2011

View full text Add to dashboard Cite

Targeting constitutively activated FMS-like tyrosine kinase 3 [(FLT3); FLT3-ITD] with tyrosine kinase inhibitor (TKI) in acute myeloid leukemia (AML) leads to clearance of blasts in the periphery but not in the bone marrow, suggesting a protective effect of the marrow niche on leukemic stem cells. In this study, we examined the effect of stromal niche cells on CD34 þ progenitors from patients with FLT3-ITD þ or wild-type FLT3 (FLT3-WT) AML treated with the TKIs SU5614 or sorafenib. TKIs effectively and specifically inhibited FLT3 and increased the fraction of undivided progenitors in both FLT3-ITD þ and FLT3-WT samples. Treatment with SU5614 and sorafenib also reduced the number of mature leukemic progenitors, whereas contact with stroma protected against this cell loss. In contrast, primitive long-term progenitors from both FLT3-ITD þ and FLT3-WT AML were resistant to TKIs. Additional contact with niche cells significantly expanded long-term FLT3-ITD þ but not FLT3-WT progenitors in the presence of SU5614 but not that of sorafenib. Thus, TKIs with first-generation inhibitors fail to eradicate early leukemic stem/progenitor cells in FLT3-ITD þ AML. Further, we defined a specific interaction between FLT3-ITD þ progenitors and niche cells that enables the maintenance of leukemic progenitors in the presence of TKI. Collectively, our findings suggest that molecular therapy may have unpredicted effects on leukemic progenitors, underscoring the necessity of developing strategies to selectively eliminate the malignant stem cell clone. Cancer Res; 71(13); 4696-706. Ó2011 AACR.

show abstract

Section: Discussionsupporting

confidence: 76%

“…Prolonged exposure of leukemic cell lines or AML blasts to TKI opts for cells that are FLT3 independent, leading to pharmacologic resistance (35,43,44). However, our results suggest that at least primitive CD34 þ FLT3-ITD þ progenitors are insensitive to TKI from the onset of treatment.…”

Section: Discussioncontrasting

confidence: 55%

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

et al. 2011

View full text Add to dashboard Cite

show abstract

“…FLT3 ligand FLT3 ligand expression was observed to be upregulated in MV4-11 cells made resistant to the FLT3 inhibitor, ABT-869, for a prolonged period of time (Zhou et al, 2009). This elevated expression led to increased protein levels of the IAP, survivin, as well as activation of STAT1, STAT3 and STAT5.…”

Section: Gain-of-function Mutations In Cblmentioning

confidence: 99%

“…This elevated expression led to increased protein levels of the IAP, survivin, as well as activation of STAT1, STAT3 and STAT5. In addition, blocking FLT3 ligand with an FLT3 ligand-neutralizing antibody was observed to enhance the proapoptotic activity of ABT-869 against ABT-869-resistant cells (Zhou et al, 2009). Another study of resistance in MV4-11 cells made resistant to PKC412 revealed acquisition of clonal alternations at chromosome 13q, additional FLT3 signaling, and changes in gene expression before and after treatment with PKC412, including that of FLT3 ligand (Stolzel et al, 2010).…”

Section: Gain-of-function Mutations In Cblmentioning

confidence: 99%

“…Aberrant expression of antiapoptotic proteins is another mechanism of resistance to FLT3 inhibitors. For example, increased protein levels of the inhibitor of apoptosis (IAP), survivin, as well as activation of STAT1, STAT3 and STAT5, were observed in ABT-869-resistant MV4-11 cells (Zhou et al, 2009), and antiapoptotic proteins were upregulated in PKC412-resistant MV4-11 cells (Stolzel et al, 2010). Similarly, overexpression of antiapoptotic proteins of the BCL2 family has been found to mediate resistance to FLT3 inhibition in hematopoietic cells with activating FLT3 mutations Mechanisms of resistance to FLT3 inhibition E Weisberg et al (Kohl et al, 2007) and the antiapoptotic protein, MCL-1, was observed to be induced by a non-juxtamembrane ITD that has integrated into the b-2 sheet of the first kinase domain (FLT3_ITD627E) (Brietenbuecher et al, 2009).…”

Section: Aberrant Activation Of Growth and Viability Pathwaysmentioning

confidence: 99%

See 1 more Smart Citation

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

Road to ABT‐869: A Multitargeted Receptor Tyrosine Kinase Inhibitor

Michaelides

Albert

2009

Kinase Inhibitor Drugs

View full text Add to dashboard Cite

Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML

Cited by 141 publications

References 51 publications

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

Drug resistance in mutant FLT3-positive AML

Road to ABT‐869: A Multitargeted Receptor Tyrosine Kinase Inhibitor

Contact Info

Product

Resources

About