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Targeting TTK Inhibits Tumorigenesis of T-Cell Lymphoma Through Dephosphorylating p38α and Activating AMPK/mTOR

Bingyu Liu1, Tiange Lu2, Mengfei Ding2

  • 1Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 21, 2025
PubMed

Insights

Threonine tyrosine kinase (TTK) is a novel therapeutic target for T-cell lymphoma (TCL). Inhibiting TTK demonstrates anti-tumor effects and improves prognosis in TCL patients by modulating the p38α pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • T-cell lymphoma (TCL) presents high heterogeneity and poor prognosis.
  • Current treatments for TCL offer limited efficacy, necessitating novel drug targets.
  • Aberrant threonine tyrosine kinase (TTK) expression is identified in TCL.

Purpose of the Study:

  • To investigate the role of TTK in T-cell lymphoma pathogenesis.
  • To evaluate TTK as a potential therapeutic target for TCL.
  • To elucidate the molecular mechanisms underlying TTK's function in TCL.

Main Methods:

  • Multi-omics analysis to identify aberrant gene expression.
  • In vitro and in vivo gene knockdown studies targeting TTK.
  • Phosphoproteomic quantification and motif prediction to identify TTK substrates.
  • Pharmacological inhibition of TTK using CFI-402257 and combination therapy with Duvelisib.

Main Results:

  • High TTK expression correlates with poor prognosis in TCL patients.
  • Targeting TTK inhibits TCL cell proliferation, induces G2/M arrest, enhances DNA damage, and promotes apoptosis.
  • TTK phosphorylates p38α, and its inhibition dephosphorylates p38α at Thr180/Tyr182, activating the AMPK/mTOR pathway and enhancing autophagy.
  • CFI-402257 exhibits anti-tumor effects and synergistic efficacy with Duvelisib in TCL.

Conclusions:

  • TTK plays a crucial role in TCL development by regulating the p38α-mediated AMPK/mTOR pathway.
  • Targeting TTK represents a promising therapeutic strategy for T-cell lymphoma.
  • CFI-402257 shows potential as a novel agent for TCL treatment, possibly in combination therapies.
Keywords:
T‐cell lymphomap38αphosphorylationthreonine tyrosine kinaseubiquitination

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