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Small Molecule Therapeutics

Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo

Katia Beider, Merav Darash-Yahana, Orly Blaier, Maya Koren-Michowitz, Michal Abraham, Hanna Wald, Ori Wald, Eithan Galun, Orly Eizenberg, Amnon Peled and Arnon Nagler
Katia Beider
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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Merav Darash-Yahana
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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Orly Blaier
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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Maya Koren-Michowitz
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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Michal Abraham
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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Hanna Wald
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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Ori Wald
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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Eithan Galun
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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Orly Eizenberg
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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Amnon Peled
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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Arnon Nagler
Authors' Affiliations: Hematology Division and CBB, Sheba Medical Center, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem; and Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel
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DOI: 10.1158/1535-7163.MCT-13-0410
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Abstract

Functional role of CXCR4 in chronic myelogenous leukemia (CML) progression was evaluated. Elevated CXCR4 significantly increased the in vitro survival and proliferation in response to CXCL12. CXCR4 stimulation resulted in activation of extracellular signal-regulated kinase (Erk)-1/2, Akt, S6K, STAT3, and STAT5 prosurvival signaling pathways. In accordance, we found that in vitro treatment with CXCR4 antagonist BKT140 directly inhibited the cell growth and induced cell death of CML cells. Combination of BKT140 with suboptimal concentrations of imatinib significantly increased the anti-CML effect. BKT140 induced apoptotic cell death, decreasing the levels of HSP70 and HSP90 chaperones and antiapoptotic proteins BCL-2 and BCL-XL, subsequently promoting the release of mitochondrial factors cytochrome c and SMAC/Diablo. Bone marrow (BM) stromal cells (BMSC) markedly increased the proliferation of CML cells and protected them from imatinib-induced apoptosis. Furthermore, BMSCs elevated proto-oncogene BCL6 expression in the CML cells in response to imatinib treatment, suggesting the possible role of BCL6 in stroma-mediated TKI resistance. BKT140 reversed the protective effect of the stroma, effectively promoted apoptosis, and decreased BCL6 levels in CML cells cocultured with BMSCs. BKT140 administration in vivo effectively reduced the growth of subcutaneous K562-produced xenografts. Moreover, the combination of BKT140 with low-dose imatinib markedly inhibited tumor growth, achieving 95% suppression. Taken together, our data indicate the importance of CXCR4/CXCL12 axis in CML growth and CML–BM stroma interaction. CXCR4 inhibition with BKT140 antagonist efficiently cooperated with imatinib in vitro and in vivo. These results provide the rational basis for CXCR4-targeted therapy in combination with TKI to override drug resistance and suppress residual disease. Mol Cancer Ther; 13(5); 1–15. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received May 22, 2013.
  • Revision received January 17, 2014.
  • Accepted January 27, 2014.
  • ©2014 American Association for Cancer Research.
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Published OnlineFirst April 22, 2014
doi: 10.1158/1535-7163.MCT-13-0410

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Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo
Katia Beider, Merav Darash-Yahana, Orly Blaier, Maya Koren-Michowitz, Michal Abraham, Hanna Wald, Ori Wald, Eithan Galun, Orly Eizenberg, Amnon Peled and Arnon Nagler
Mol Cancer Ther April 22 2014 DOI: 10.1158/1535-7163.MCT-13-0410

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Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo
Katia Beider, Merav Darash-Yahana, Orly Blaier, Maya Koren-Michowitz, Michal Abraham, Hanna Wald, Ori Wald, Eithan Galun, Orly Eizenberg, Amnon Peled and Arnon Nagler
Mol Cancer Ther April 22 2014 DOI: 10.1158/1535-7163.MCT-13-0410
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