Ciclosporin A potentiates venetoclax efficacy in FLT3-ITD AML by targeting the NFATC1-AKT-mTOR-BCL-2/MCL-1 signaling axis.

The Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukaemia (AML) is associated with adverse clinical outcomes, including poor prognosis, high relapse rates and reduced responses to conventional treatment regimens. While venetoclax (VEN) monotherapy has shown limited efficacy in FLT3-ITD AML due to intrinsic resistance mechanisms, this study demonstrates that ciclosporin A (CsA) synergistically enhances VEN's anti-leukaemic activity. CsA significantly suppresses cell proliferation, induces mitochondrial apoptosis and impairs mitochondrial bioenergetics in FLT3-ITD AML cells. Mechanistically, CsA enhances the effects of VEN through the downregulation of NFATC1, a critical regulator of the PI3K/AKT/mTOR signalling pathway. This suppression of NFATC1 leads to the coordinated downregulation of the anti-apoptotic proteins BCL-2 and MCL-1, thereby overcoming resistance and reinstating therapeutic susceptibility in FLT3-ITD AML.