KTX207-mediated PDE4D degradation disrupts tumour cell migration, invasion, and angiogenic potential

BACKGROUND: Phosphodiesterase 4 (PDE4) enzymes regulate intracellular cyclic adenosine monophosphate (cAMP) and thereby influence multiple cancer-relevant processes. Metastasis and angiogenesis, which rely on coordinated cytoskeletal remodelling and integrin-mediated signalling are key determinants of cancer progression. We previously reported KTX207, a cereblon-based proteolysis-targeting chimera (PROTAC) that selectively degrade PDE4D shortforms and suppresses tumour cell proliferation. METHODS: To further evaluate the therapeutic potential of KTX207, we examined the effects of PDE4D degradation on cancer cell migration, invasion, cytoskeletal organisation, and angiogenic capacity using 2D and 3D models. Assays included wound healing, Boyden chamber invasion, single-cell tracking, 3D spheroid invasion, endothelial tube formation and sprouting assays, as well as immunocytochemistry, Western blotting, and ELISA. Proteasome inhibition was used to assess degradation dependency. RESULTS: KTX207 markedly impaired A549 cell motility, abrogated directional persistence, disrupted cytoskeletal architecture with mislocalisation of focal adhesion kinase, and reduced invasive capability. Endothelial cells exhibited reduced angiogenic and sprouting potential. KTX207 altered key regulators of focal adhesion and cytoskeletal signalling, including integrin β1, ezrin, RhoA, and phospho‑Src, and reduced angiogenic factors such as VEGF‑A and angiopoietin‑2. Phospho-FAK levels remained unchanged, indicating disruption of spatial rather than global kinase signalling. Importantly, these effects were attenuated by proteasome inhibition, supporting a degradation-dependent mechanism. CONCLUSION: These findings highlight a previously underappreciated role for PDE4D shortforms in coordinating cytoskeletal dynamics and tumour-associated angiogenesis. Targeted PDE4D degradation therefore represents a promising therapeutic strategy for limiting metastatic progression.