Cyclosporine A Enhances the Efficacy of Venetoclax Against FLT3-ITD AML via the PI3K/AKT/mTOR Signaling Pathway

Acute myeloid leukemia (AML) with the Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation accounts for approximately 25-30% of cases and is associated with a poor prognosis, characterized by high relapse rates and significantly reduced overall survival. The use of single-agent venetoclax in FLT3-ITD AML has shown limited efficacy, with drug resistance frequently emerging. In this study, we demonstrate that cyclosporine A (CsA) sensitizes FLT3-ITD AML cells to venetoclax by inhibiting cell proliferation, promoting apoptosis, and disrupting mitochondrial function. Mechanistically, CsA enhances the anti-AML effects of venetoclax by inhibiting NFATC1 through the PI3K/AKT/mTOR signaling pathway. These findings offer promising new therapeutic strategies for managing refractory and relapsed AML, providing a basis for future combination therapies targeting FLT3-ITD mutations. Overall design: To study the effects of venetoclax and CSA combination treatment on FLT3-ITD cells, we set up the following groups: control group, venetoclax monotherapy group, CSA monotherapy group, and venetoclax + CSA combination treatment group, treating MV4-11 cells for 24 hours. Then, we performed gene expression profiling analysis on the RNA data obtained from the four groups.