title: Combination of imatinib with CXCR4 antagonist BKT140 overcomes the protective effect of stroma and targets CML in vitro and in vivo.
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.
authors: 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.
authors: Katia
authors: K
authors: Beider
authors: Merav
authors: M
authors: Darash-Yahana
authors: Orly
authors: O
authors: Blaier
authors: Maya
authors: M
authors: Koren-Michowitz
authors: Michal
authors: M
authors: Abraham
authors: Hanna
authors: H
authors: Wald
authors: Ori
authors: O
authors: Wald
authors: Eithan
authors: E
authors: Galun
authors: Orly
authors: O
authors: Eizenberg
authors: Amnon
authors: A
authors: Peled
authors: Arnon
authors: A
authors: Nagler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: C577220:BKT140; D001549:Benzamides; D054377:Chemokine CXCL12; C000715470:MAS1 protein, human; D009842:Oligopeptides; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines; D019718:Receptors, CXCR4; D000068877:Imatinib Mesylate