title: Janus kinase inhibition by ruxolitinib extends dasatinib- and dexamethasone-induced remissions in a mouse model of Ph+ ALL.
abstract: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is initiated and driven by the oncogenic fusion protein BCR-ABL, a constitutively active tyrosine kinase. Despite major advances in the treatment of this highly aggressive disease with potent inhibitors of the BCR-ABL kinase such as dasatinib, patients in remission frequently relapse due to persistent minimal residual disease possibly supported, at least in part, by salutary cytokine-driven signaling within the hematopoietic microenvironment. Using a mouse model of Ph+ ALL that accurately mimics the genetics, clinical behavior, and therapeutic response of the human disease, we show that a combination of 2 agents approved by the US Food and Drug Administration (dasatinib and ruxolitinib, which inhibit BCR-ABL and Janus kinases, respectively), significantly extends survival by targeting parallel signaling pathways. Although the BCR-ABL kinase cancels the cytokine requirement of immature leukemic B cells, dasatinib therapy restores cytokine dependency and sensitizes leukemic cells to ruxolitinib. As predicted, ruxolitinib alone had no significant antileukemic effect in this model, but it prevented relapse when administered with dasatinib. The combination of dasatinib, ruxolitinib, and the corticosteroid dexamethasone yielded more durable remissions, in some cases after completion of therapy, avoiding the potential toxicity of other cytotoxic chemotherapeutic agents.
authors.affiliation: Cancer Biology & Genetics Program, and.
authors.forename: Iris
authors.initials: I
authors.lastname: Appelmann
authors.affiliation: Cancer Biology & Genetics Program, and.
authors.forename: Cory D
authors.initials: CD
authors.lastname: Rillahan
authors.affiliation: Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY; and.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY; and.
authors.forename: Gregory
authors.initials: G
authors.lastname: Carbonetti
authors.affiliation: Cancer Biology & Genetics Program, and.
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Cancer Biology & Genetics Program, and Howard Hughes Medical Institute, and.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.affiliation: Cancer Biology & Genetics Program, and Howard Hughes Medical Institute, and Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Charles J
authors.identifier: http://orcid.org/0000-0002-5516-6206
authors.initials: CJ
authors.lastname: Sherr
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000502:physiology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D000069439:Dasatinib; D003907:Dexamethasone / Q000008:administration & dosage; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009570:Nitriles; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D013844:Thiazoles / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
chemical_list: D015851:Interleukin-7; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013844:Thiazoles; D003907:Dexamethasone; C540383:ruxolitinib; D016044:Fusion Proteins, bcr-abl; D053612:Janus Kinases; D020823:ADP-Ribosylation Factor 1; D000069439:Dasatinib