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

by Selleckchem | Jun 19 2023

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.

Comments:

The study focuses on the identification and understanding of mechanisms of resistance to the JAK/TYK2 inhibitor (JAKi) cerdulatinib in high-risk acute lymphoblastic leukemia (HR-ALL) cases with TYK2 rearrangements. TYK2-rearranged HR-ALL is characterized by the presence of a fusion oncogene called MYB-TYK2, which leads to constitutive activation of the JAK/STAT signaling pathway.

In pre-clinical studies using TYK2-rearranged ALL cells, cerdulatinib was found to be effective in attenuating the aberrant JAK/STAT signaling caused by the TYK2 fusion protein. However, over time, the ALL cells developed resistance to cerdulatinib, leading to relapse in patients.

The researchers generated cerdulatinib-resistant B-cells in the laboratory by exposing the MYB-TYK2-rearranged ALL cells to the drug for an extended period. Continued treatment with cerdulatinib resulted in sustained JAK/STAT signaling and the overexpression of the JAK1 protein. These changes were reversible when cerdulatinib was withdrawn, indicating that the resistance mechanism was dynamic and dependent on continued exposure to the drug.

Importantly, the study also explored alternative therapeutic approaches for TYK2-rearranged B-ALL patients who had developed resistance to JAKi treatment. The researchers found that histone deacetylase inhibitor (HDACi) therapies were effective against the cerdulatinib-resistant cells. HDAC inhibitors are known to modify the structure of chromatin and can affect gene expression patterns. By targeting HDACs, these inhibitors could potentially reverse the resistance to cerdulatinib and provide an alternative treatment option for patients who have lost responsiveness to JAKi regimens.

Overall, the study provides valuable insights into the mechanisms of resistance to cerdulatinib in TYK2-rearranged ALL cells and suggests that HDAC inhibitors could be a potential alternative therapy for patients who relapse or develop resistance to JAKi treatment. However, it is important to note that further research and clinical trials are necessary to validate these findings and determine the optimal therapeutic strategies for TYK2-rearranged B-ALL patients.