Janus kinase inhibition by ruxolitinib extends dasatinib- and dexamethasone-induced remissions in a mouse model of Ph+ ALL Journal Article

Authors: Appelmann, I.; Rillahan, C. D.; de Stanchina, E.; Carbonetti, G.; Chen, C.; Lowe, S. W.; Sherr, C. J.
Article 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. © 2015 by The American Society of Hematology.
Keywords: signal transduction; survival rate; genetics; mutation; mortality; antineoplastic agent; mouse; animal; metabolism; animals; mice; stat3 protein; reverse transcription polymerase chain reaction; neoplasm recurrence, local; antineoplastic combined chemotherapy protocols; interleukin 7; dexamethasone; drug resistance; pathology; tumor cell culture; drug resistance, neoplasm; tumor cells, cultured; dasatinib; pyrimidines; mice, inbred c57bl; physiology; c57bl mouse; disease model; blotting, western; messenger rna; reverse transcriptase polymerase chain reaction; rna, messenger; janus kinase; pyrazole derivative; tumor recurrence; pyrazoles; western blotting; remission; remission induction; precursor cell lymphoblastic leukemia-lymphoma; stat3 transcription factor; real time polymerase chain reaction; bcr abl protein; disease models, animal; pyrimidine derivative; thiazoles; fusion proteins, bcr-abl; interleukin-7; philadelphia 1 chromosome; philadelphia chromosome; thiazole derivative; adenosine diphosphate ribosylation factor 1; stat3 protein, mouse; janus kinases; adp-ribosylation factor 1; real-time polymerase chain reaction; drug effects; ruxolitinib; humans; human; male; female; antagonists and inhibitors
Journal Title: Blood
Volume: 125
Issue: 9
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2015-02-26
Start Page: 1444
End Page: 1451
Language: English
DOI: 10.1182/blood-2014-09-601062
PUBMED: 25499760
PROVIDER: scopus
PMCID: PMC4342356
Notes: Article -- Export Date: 2 June 2016 -- Source: Scopus
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MSK Authors
  1. Scott W Lowe
    149 Lowe
  2. Charles J. Sherr
    2 Sherr
  3. Chong Chen
    11 Chen