Selective HDAC6 inhibitor WT161 modulates the VLA-4/FAK pathway by inhibiting PKA activity in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous malignancy often associated with poor prognosis due to chemotherapy resistance and relapse. Histone deacetylase (HDAC) inhibitors represent an emerging class of epigenetic antitumor drugs. Among them, HDAC6, which is an enzyme that deacetylates α-tubulin, is increasingly recognized as a potential therapeutic target in hematologic malignancies. The adhesion molecule very late antigen 4 (VLA-4) plays a key role in cell adhesion-mediated drug resistance (CAMDR). We hypothesized that inhibiting HDAC6 could counteract CAMDR mediated by crosstalk between α-tubulin and integrin signaling. This study therefore investigated the therapeutic potential of WT161, a selective HDAC6 inhibitor, focusing on its role in targeting of the VLA-4/Focal adhesion kinase (FAK) signaling pathway in ALL. Human B-ALL (BALL-1, NALM6) and T-ALL (Jurkat, MOLT-4) cell lines were treated with WT161, and its effects on proliferation, adhesion, migration, apoptosis, and cell cycle progression were evaluated. Protein expression and phosphorylation were analyzed by Western blot, and VLA-4 expression was assessed using immunofluorescence. In vivo, NOD/SCID mice xenografted with ALL cells were treated with WT161, vincristine, or their combination. WT161 significantly inhibited proliferation, reduced adhesion and migration, and induced apoptosis in ALL cells. Mechanistically, it decreased intracellular cAMP levels, thereby inhibiting Protein kinase A (PKA) activity and suppressing the FAK signaling pathway. In xenograft models, WT161 exhibited anti-tumor effects, which were enhanced in combination with vincristine. This study highlights WT161's therapeutic potential in ALL, demonstrating its ability to inhibit PKA activity and disrupt the VLA-4/FAK pathway, thereby offering a promising novel strategy for ALL treatment.