title: Inhibition of calcineurin combined with dasatinib has direct and indirect anti-leukemia effects against BCR-ABL1(+) leukemia.
abstract: Treatment of BCR-ABL1(+) leukemia has been revolutionized with the development of tyrosine kinase inhibitors. However, patients with BCR-ABL1(+) acute lymphoblastic leukemia and subsets of patients with chronic myeloid leukemia are at high risk of relapse despite kinase inhibition therapy, necessitating novel treatment strategies. We previously reported synthetic lethality in BCR-ABL1(+) leukemia cells by blocking both calcineurin/NFAT signaling and BCR-ABL1, independent of drug efflux inhibition by cyclosporine. Here, using RNA-interference we confirm that calcineurin inhibition sensitizes BCR-ABL1(+) cells to tyrosine kinase inhibition in vitro. However, when we performed pharmacokinetic and pharmacodynamic studies of dasatinib and cyclosporine in mice, we found that co-administration of cyclosporine increases peak concentrations and the area under the curve of dasatinib, which contributes to the enhanced disease control. We also report the clinical experience of two subjects in whom we observed more hematopoietic toxicity than expected while enrolled in a Phase Ib trial designed to assess the safety and tolerability of adding cyclosporine to dasatinib in humans. Thus, the anti-leukemia benefit of co-administration of cyclosporine and dasatinib is mechanistically pleiotropic, but may not be tolerable, at least as administered in this trial. These data highlight some of the challenges associated with combining targeted agents to treat leukemia.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Gardner
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Jelena
authors.initials: J
authors.lastname: Klawitter
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gregory
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Vadym
authors.initials: V
authors.lastname: Zaberezhnyy
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Baturin
authors.affiliation: Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pollyea
authors.affiliation: Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD.
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045.|Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045.|Department of Biochemistry & Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045.|Department of Immunology, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: James
authors.initials: J
authors.lastname: DeGregori
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Porter
mesh_terms: D000328:Adult; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D065095:Calcineurin Inhibitors; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069439:Dasatinib; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013844:Thiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: C581634:BCR-ABL1 fusion protein, human; D065095:Calcineurin Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016572:Cyclosporine; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib