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Type: Journal article
Title: Constitutive JAK/STAT signaling is the primary mechanism of resistance to JAKi in TYK2-rearranged acute lymphoblastic leukemia
Author: Tavakoli Shirazi, P.
Eadie, L.N.
Page, E.C.
Heatley, S.L.
Bruning, J.B.
White, D.L.
Citation: Cancer Letters, 2021; 512:28-37
Publisher: Elsevier
Issue Date: 2021
ISSN: 0304-3835
Statement of
Paniz Tavakoli Shirazi, Laura N.Eadie, Elyse C.Page, Susan L.Heatley, John B.Bruning, Deborah L.White
Abstract: Activating TYK2-rearrangements have recently been identified and implicated in the leukemogenesis of high-risk acute lymphoblastic leukemia (HR-ALL) cases. Pre-clinical studies indicated the JAK/TYK2 inhibitor (JAKi), cerdulatinib, as a promising therapeutic against TYK2-rearranged ALL, attenuating the constitutive JAK/STAT signaling resulting from the TYK2 fusion protein. However, following a period of clinical efficacy, JAKi resistance often occurs resulting in relapse. In this study, we modeled potential mechanisms of JAKi resistance in TYK2-rearranged ALL cells in vitro in order to recapitulate possible clinical scenarios and provide a rationale for alternative therapies. Cerdulatinib resistant B-cells, driven by the MYB-TYK2 fusion oncogene, were generated by long-term exposure to the drug. Sustained treatment of MYB-TYK2-rearranged ALL cells with cerdulatinib led to enhanced and persistent JAK/STAT signaling, co-occurring with JAK1 overexpression. Hyperactivation of JAK/STAT signaling and JAK1 overexpression was reversible as cerdulatinib withdrawal resulted in re-sensitization to the drug. Importantly, histone deacetylase inhibitor (HDACi) therapies were efficacious against cerdulatinib-resistant cells demonstrating a potential alternative therapy for use in TYK2-rearranged B-ALL patients who have lost response to JAKi treatment regimens.
Keywords: Acute lymphoblastic leukemia; TYK2 rearrangements; JAKi; resistance; HDACi
Rights: © 2021 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.canlet.2021.04.027
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