title: Dasatinib inhibits CXCR4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards CXCL12.
abstract: Chemokines and their ligands play a critical role in enabling chronic lymphocytic leukaemia (CLL) cells access to protective microenvironmental niches within tissues, ultimately resulting in chemoresistance and relapse: disruption of these signaling pathways has become a novel therapeutic approach in CLL. The tyrosine kinase inhibitor dasatinib inhibits migration of several cell lines from solid-organ tumours, but effects on CLL cells have not been reported. We studied the effect of clinically achievable concentrations of dasatinib on signaling induced by the chemokine CXCL12 through its' receptor CXCR4, which is highly expressed on CLL cells. Dasatinib pre-treatment inhibited Akt and ERK phosphorylation in CLL cells upon stimulation with CXCL12. Dasatinib also significantly diminished the rapid increase in actin polymerisation observed in CLL cells following CXCL12 stimulation. Moreover, the drug significantly inhibited chemotaxis in a transwell assay, and reduced the percentage of cells able to migrate beneath a CXCL12-expressing murine stromal cell line. Dasatinib also abrogated the anti-apoptotic effect of prolonged CXCL12 stimulation on cultured CLL cells. These data suggest that dasatinib, akin to other small molecule kinase inhibitors targeting the B-cell receptor signaling pathway, may redistribute CLL cells from protective tissue niches to the peripheral blood, and support the investigation of dasatinib in combination strategies.
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. Alison.mccaig@ggc.scot.nhs.uk
authors.forename: Alison M
authors.initials: AM
authors.lastname: McCaig
authors.forename: Emilio
authors.initials: E
authors.lastname: Cosimo
authors.forename: Michael T
authors.initials: MT
authors.lastname: Leach
authors.forename: Alison M
authors.initials: AM
authors.lastname: Michie
mesh_terms: D000199:Actins / Q000737:chemistry; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000069439:Dasatinib; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000199:Actins; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019718:Receptors, CXCR4; D013844:Thiazoles; D048049:Extracellular Signal-Regulated MAP Kinases; D000069439:Dasatinib