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Cited by 150Chronic Myeloid Leukemia TreatmentsProtein Tyrosine PhosphatasesChronic Lymphocytic Leukemia Research

Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance

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Bewry, Nadine N., Nair, Rajesh R., Emmons, Michael F., Boulware, David, Pinilla-Ibarz, Javier, Hazlehurst, Lori A.·2008·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.mct-08-0314PMC PMC2676735
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Abstract

Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenvironment of CML and is a rich source of both soluble factors and extracellular matrices, which may influence drug response. To address the influence of the bone marrow microenvironment on imatinib mesylate sensitivity, we used an in vitro bone marrow stroma model. Our data show culturing K562 cells, in bone marrow stroma-derived conditioned medium (CM), is sufficient to cause resistance to BCR-ABL inhibitors. Drug resistance correlated with increased pTyrStat3, whereas no increases in pTyrStat5 was noted. Moreover, resistance was associated with increased levels of the Stat3 target genes Bcl-xl, Mcl-1, and survivin. Finally, reducing Stat3 levels with small interfering RNA sensitized K562 cells cultured in CM to imatinib mesylate-induced cell death. Importantly, Stat3 dependency was specific for cells grown in CM, as reducing Stat3 levels in regular growth conditions had no effect on imatinib mesylate sensitivity. Together, these data support a novel mechanism of BCR-ABL-independent imatinib mesylate resistance and provides preclinical rationale for using Stat3-inhibitors to increase the efficacy of imatinib mesylate within the context of the bone marrow microenvironment. [Mol Cancer Ther 2008;7(10):3169–75]

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  • STAT3 inhibition may also be effective at overcoming targeted therapy resistance in hematological malignancies.

    “Knockdown of STAT3 by small interfering RNA in this context resensitizes the cells to imatinib mesylate-induced cell death, suggesting that STAT3 inhibition may also be effective at overcoming targeted therapy resistance in hematological malignancies.110”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [110]

    The Results section reports that STAT3 siRNA sensitized K562 leukemia cells to imatinib-induced death, but only in bone marrow stroma-derived conditioned medium. The Discussion presents this as a rationale for further testing STAT3 inhibitors with BCR-ABL inhibitors; the broader suggestion about targeted-therapy resistance across hematological malignancies remains untested in this paper. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Knockdown of STAT3 by small interfering RNA resensitizes cells to imatinib mesylate-induced cell death.

    “Knockdown of STAT3 by small interfering RNA in this context resensitizes the cells to imatinib mesylate-induced cell death, suggesting that STAT3 inhibition may also be effective at overcoming targeted therapy resistance in hematological malignancies.110”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [110]

  • Resistance to imatinib mesylate in chronic myeloid leukemia cell models is associated with increased STAT3 activation and target gene expression.

    “Likewise, resistance to the tyrosine kinase inhibitor imatinib mesylate, which targets the BCR-ABL oncoprotein, in chronic myeloid leukemia cell models is also associated with increased STAT3 activation and target gene expression.110”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [110]

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Research works printed but not linked: 33

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Cited by

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Authors
Bewry, N. N., Nair, R. R., Emmons, M. F., Boulware, D., Pinilla-Ibarz, J., & Hazlehurst, L. A.
Affiliations
  • University of South Florida (US)
  • 1Molecular Oncology Program,
  • 3Biostatistics Division,
  • Moffitt Cancer Center (US)
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2008-10-01
Volume
7
Issue
10
Pages
3169-3175
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.mct-08-0314
PMC
PMC2676735
OpenAlex
W2114210071
Cited by
150
References
1
Citations by year
2026: 1 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 12 · 2020: 13 · 2019: 12 · 2018: 6 · 2017: 8 · 2016: 10 · 2015: 19 · 2014: 11 · 2013: 18 · 2012: 10
FWCI
3.70
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Cancer Research Institute
  • Moffitt Cancer Center
  • Novartis Pharma
  • National Cancer Institute (CA5R01CA122065-02, R01CA122065)
Topics
  • Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
Keywords
STAT3, imatinib resistance, BCR-ABL tyrosine kinase inhibitors, chronic myeloid leukemia, bone marrow microenvironment, bone marrow stroma, K562 cells, STAT5, Bcl-xL, Mcl-1, survivin, STAT3 inhibitor, drug resistance
MeSH terms
Imatinib Mesylate, Dasatinib, Benzamides, Bone Marrow, Humans, Piperazines, Pyrimidines, Thiazoles, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Gene Expression Regulation, Leukemic, Fusion Proteins, bcr-abl, Cell Death, Culture Media, Conditioned, Phosphotyrosine, Drug Resistance, Neoplasm, RNA, Small Interfering, Cell Line, Tumor, Protein Kinase Inhibitors, STAT3 Transcription Factor

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