Constitutive JAK/STAT signaling is the primary mechanism of resistance to JAKi in TYK2-rearranged acute lymphoblastic leukemia

Cancer Lett. 2021 Aug 1:512:28-37. doi: 10.1016/j.canlet.2021.04.027. Epub 2021 May 7.

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; HDACi; JAKi; Resistance; TYK2 rearrangements.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Resistance, Neoplasm
  • Gene Rearrangement
  • Humans
  • Janus Kinase Inhibitors / pharmacology*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Proto-Oncogene Proteins c-myb / genetics
  • Proto-Oncogene Proteins c-myb / metabolism
  • Pyrimidines / pharmacology
  • STAT Transcription Factors / metabolism*
  • Signal Transduction
  • Sulfones / pharmacology
  • TYK2 Kinase / genetics*
  • TYK2 Kinase / metabolism

Substances

  • 4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide
  • Janus Kinase Inhibitors
  • MYB protein, human
  • Proto-Oncogene Proteins c-myb
  • Pyrimidines
  • STAT Transcription Factors
  • Sulfones
  • TYK2 Kinase
  • TYK2 protein, human