Saptaswa Dey Saptaswa Dey Helena Sorger (Centre of Biological Sciences, Department of Biological Sciences and Pathobiology, Departments, University of Veterinary Medicine Vienna) Helena Sorger Michaela Schlederer Michaela Schlederer Isabella Perchthaler Isabella Perchthaler Martin Metzelder Martin Metzelder Lukas Kenner (Centre of Pathobiology, Department of Biological Sciences and Pathobiology, Departments, University of Veterinary Medicine Vienna) Lukas Kenner Richard Moriggl (Centre of Biological Sciences, Department of Biological Sciences and Pathobiology, Departments, University of Veterinary Medicine Vienna) Richard Moriggl Peter Wolf Peter Wolf Frontiers Media SA 2026 Background: ‘Cutaneous T-cell lymphoma (CTCL), particularly tumor stage mycosis fungoides (MF), presents significant therapeutic challenges due to limited treatment efficacy. This study addresses the unmet need for novel targeted therapies targeting the constitutively hyperactive STAT3/5 pathway. Methods: Kinome-wide profiling revealed that IQDMA selectively inhibits PAK2 (69%) and JAK3 (61%), kinases critical for STAT5 nuclear transport and activation. Using a C57BL/6 intradermal T-cell lymphoma model, we evaluated IQDMA efficacy against conventional psoralen + UV-A (PUVA) phototherapy. Results: IQDMA reduced tumor volume by 90.7% (P = 0.0001), significantly outperforming PUVA (46.2%, P = 0.0074). Immunohistochemical analysis demonstrated 45.6% and 40.0% reductions in STAT3+ (P = 0.01) and STAT5+ (P = 0.0478) tumor cells, respectively. Strikingly, while phospho-STAT5 (pY-STAT5) and total STAT5 positively correlated in vehicle-treated tumors (r = +0.57), IQDMA treatment inverted this relationship to a significant negative correlation (r = −0.74, P = 0.046), with pY-STAT5 redistributing from nucleus to cytoplasm—indicating disruption of STAT5 nuclear transport. Quantitative proteomics identified CDC42, the obligate scaffold for PAK2 activation, as the only mechanistically critical protein achieving statistical significance (Hedges’ g = −4.49, FDR = 0.032). Downstream, CCND2 (Cyclin D2)—a direct STAT5 transcriptional target—showed 86% reduction, confirming functional STAT5 blockade. Kinase-substrate network analysis revealed PAK1 substrates were 4.9-fold enriched among downregulated proteins (OR = 4.91, P = 0.011), validating the PAK-STAT axis as IQDMA’s primary mechanism. Conclusion: These findings establish a CDC42-PAK-STAT nuclear transport axis wherein IQDMA simultaneously inhibits PAK2 kinase activity and depletes its CDC42 scaffold, creating cytoplasmic pY-STAT5 retention that uncouples phosphorylation from transcriptional execution—a dual mechanism distinct from selective JAK inhibitors that warrants clinical evaluation. PDFDocument eng 2026-08-19T08:01:33.373745752Z 2026 CDC42 Cutaneous T-cell Lymphoma Multi-kinase Inhibitor Mycosis Fungoides Nuclear Transporter PAK Kinase Quantitative Proteomics STAT3 And STAT5 31779327 b application/pdf http://creativecommons.org/licenses/by/4.0/