Therapeutic Targeting of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway in Cutaneous T-Cell Lymphoma

Abstract

Background/Objectives: Cutaneous T-cell lymphoma (CTCL) is a rare group of non-Hodgkin lymphomas characterized by the clonal expansion of malignant T cells. While current treatments can alleviate symptoms and significant progress has been made in treating leukemic CTCL, a definitive cure remains elusive. Dysregulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a key driver of CTCL pathogenesis. As a result, therapeutic strategies targeting JAK/STAT signaling have gained momentum, with the increasing use of JAK inhibitors and other agents that effectively suppress this pathway. These immune-modulating therapies have broad effects on physiological processes, inflammation, and the pathological changes associated with both inflammatory diseases and cancers. Several JAK inhibitors, originally FDA-approved for inflammatory conditions, are now being investigated for cancer treatment. Methods: In this paper, a brief review of the literature on JAK/STAT pathway dysregulation in CTCL is provided, highlighting both clinical and preclinical studies involving JAK inhibitors and other agents that target this pathway. Results: Specifically, we focus on six JAK inhibitors currently under clinical investigation-golidocitinib, ruxolitinib, cerdulatinib, tofacitinib, upadacitinib, and abrocitinib. Additionally, we discuss preclinical studies that explore the mechanisms underlying JAK/STAT pathway inhibition in CTCL. Furthermore, we review reported cases in which CTCL relapsed or emerged following JAK inhibitor treatment. Conclusions: Collectively, these findings support the potential clinical utility of targeting the JAK/STAT pathway in CTCL. However, further research is needed to evaluate safety risks, minimize adverse effects, and optimize these therapeutic strategies.

Keywords: JAK/STAT inhibitors; JAK/STAT pathway; Sézary syndrome; adverse effects; clinical response; cutaneous T-cell lymphoma; mycosis fungoides; pathogenesis; therapeutic strategies.

Figure 1

The diagram of the cytokine-mediated JAK/STAT signaling pathway and potential targets of inhibition of the pathway. ① Upon binding of cytokines to the cytokine receptors, the signal transduction process is initiated. Cytokine-mediated receptor dimerization leads to ② the recruitment and activation of JAKs by phosphorylating tyrosine residues; ③ Activated JAKs recruit and phosphorylate STATs, ④ that then dimerize and ⑤ translocate to the nucleus. In the nucleus, STATs bind to STAT-binding promoter in the DNA, leading to the transcription of cytokine responsive genes. There are a few negative regulators along the JAK/STAT signaling pathway: suppressors of cytokine signaling proteins (SOCS) inhibit JAKs by acting as pseudo-JAK substrates, while protein tyrosine phosphatases (PTPs) down-regulate the pathway by dephosphorylating JAK/STAT components; protein inhibitors of activated STATs (PIASs) can interact with activated STATs and inhibit their DNA binding and their transactivating capacity. Therapeutic targets of JAK inhibitors and agents inhibiting the JAK/STAT signaling are indicated. This presentation was created in BioRender. Ni, X. (2025) https://BioRender.com/h10d557 (accessed on 29 January 2025).