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https://hdl.handle.net/2440/131690
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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 1872-7980 |
Statement of Responsibility: | 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 |
Grant ID: | NHMRC |
Published version: | http://dx.doi.org/10.1016/j.canlet.2021.04.027 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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