Combination of Imatinib with CXCR4 antagonist BKT140 overcomes the protective effect of stroma and targets CML in vitro and in vivo
Menée in vitro et in vivo, cette étude évalue l'activité d'un composé appelé BKT140, un inhibiteur de CXCR4, en combinaison avec l'imatinib pour le traitement d'une leucémie myéloïde chronique
Functional role of CXCR4 in CML progression was evaluated. Elevated CXCR4 significantly increased the in vitro survival and proliferation in response to CXCL12. CXCR4 stimulation resulted in activation of Erk1/2, Akt, S6K, STAT3 and STAT5 pro-survival 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 sub-optimal concentrations of imatinib significantly increased the anti-CML effect. BKT140 induced apoptotic cell death, decreasing the levels of HSP70 and HSP90 chaperons and anti-apoptotic proteins BCL-2 and BCL-XL, subsequently promoting the release of mitochondrial factors cytochrome c and SMAC/Diablo. BM stromal cells markedly increased the proliferation of CML cells and protected them from imatinib-induced apoptosis. Furthermore, BM stromal cells 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 co-cultured 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.
http://mct.aacrjournals.org/content/early/2014/02/06/1535-7163.MCT-13-0410.abstract