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Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
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IQDMA disrupts STAT5 nuclear transport through CDC42-PAK2 axis collapse in cutaneous T-cell lymphoma

Saptaswa Dey1,2,3, Helena Sorger4,5, Michaela Schlederer2

  • 1Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.

Frontiers in Immunology
|April 2, 2026
PubMed
Abstract

Insights

IQDMA significantly reduced tumor volume in a cutaneous T-cell lymphoma model by inhibiting the PAK-STAT pathway. This novel dual-action therapy disrupts STAT5 nuclear transport, offering a promising new treatment for mycosis fungoides.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cutaneous T-cell lymphoma (CTCL), particularly mycosis fungoides (MF), has limited treatment options.
  • Hyperactive STAT3/5 signaling is a key driver in CTCL.
  • Novel targeted therapies are needed for advanced MF.

Purpose of the Study:

  • To evaluate the efficacy of IQDMA, a novel inhibitor targeting the STAT3/5 pathway.
  • To investigate IQDMA's mechanism of action in a CTCL model.
  • To compare IQDMA with conventional psoralen + UV-A (PUVA) phototherapy.

Main Methods:

  • Kinome-wide profiling identified IQDMA's targets: PAK2 and JAK3.
  • IQDMA efficacy was tested in a C57BL/6 intradermal T-cell lymphoma model.
  • Tumor volume, STAT3/5 expression, and protein interactions were analyzed.

Main Results:

  • IQDMA achieved a 90.7% reduction in tumor volume, significantly outperforming PUVA (46.2%).
  • IQDMA decreased STAT3+ and STAT5+ tumor cells and disrupted STAT5 nuclear transport.
  • Quantitative proteomics identified CDC42 as a critical scaffold protein for IQDMA's action.

Conclusions:

  • IQDMA establishes a novel CDC42-PAK-STAT nuclear transport axis.
  • It simultaneously inhibits PAK2 and depletes its CDC42 scaffold, blocking STAT5 activation.
  • This dual mechanism warrants clinical evaluation for CTCL treatment.
Keywords:
CDC42PAK kinaseSTAT3 and STAT5cutaneous T-cell lymphomamulti-kinase inhibitormycosis fungoidesnuclear transporterquantitative proteomics

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