Abstract
BACKGROUND: T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive hematologic malignancy characterized by drug resistance, relapse and poor prognosis. Chidamide, a histone deacetylase inhibitor, has shown epigenetic therapeutic potential in T-ALL, but its efficacy is limited and acquired drug resistance exists. To overcome these limitations, we systematically evaluated the synergistic Combination effects of three drug candidates, OTX-015 (BET inhibitor), Metformin (metabolic regulator), and Anlotinib (multitargeted tyrosine kinase inhibitor), with Chidamide. METHODS: We chose Jurkat cells, a cell line for T-ALL, for our experiments. With the CCK-8 trial, we chose the most efficacious Combination of Anlotinib and Chidamide, for the follow-up trial. The antitumor activity of Chidamide and Anlotinib alone or in Combination on Jurkat cells was detected by cell proliferation, apoptosis and cell cycle assay. Transcriptome sequencing and Western blotting were used to identify the key signaling pathways. RESULTS: Jurkat cells treated with Anlotinib showed significant inhibition of cell viability, G2/M arrest and apoptosis. Combination therapy with Chidamide synergistically potentiates these effects. Mechanistically, the Combination treatment inhibited the components of the Hippo pathway (CCN2 and YAP), suppressed the PI3K-Akt signaling pathway, and remodeled the expression of extracellular matrix (ECM) -related genes. Transcriptomic analysis further highlighted the enrichment of ECM organization and PI3K-Akt pathway. CONCLUSIONS: Chidamide and Anlotinib synergistically inhibit Hippo signaling pathway, which reveals a novel "dual epigenetic kinase targeting" strategy for the treatment of T-ALL. Future studies should validate these findings in vivo and investigate the impact of the metabolic microenvironment on therapeutic efficacy.