CCBIO and CMYC seminar

“Stress for success”: Unlocking Venetoclax sensitivity in T-ALL through the mTORC1–ISR–BMF axis.

by Prof. Vincenzo Ciminale, MD, Istituto Oncologico Veneto, Padova, Italy

When: Thursday, 13.11.2025, 14.30–15.30

Where: Aud. 4, BBB

Host: Bjørn Tore Gjertsen

Abstract

Refractory/relapsed T-cell acute lymphoblastic leukemia (R/R T-ALL) remains a major therapeutic challenge at present. Our recent studies showed that inhibition of mTORC1 markedly sensitizes T-ALL cell lines and patient-derived xenografts (PDXs) to the BCL-2 inhibitor Venetoclax. RNAseq, gene set enrichment analysis, and analysis of the temporal trajectories of response to the mTORC1 inhibitor Everolimus revealed that induction of cell death was dependent on sustained engagement of the integrated stress response (ISR), resulting in induction of BMF, a proapoptotic protein of the BCL-2 family. The effects on cell death were phenocopied by the bisteric mTORC1 inhibitor RMC6272 or by genetic silencing of the mTORC1 cofactor Raptor. Genetic silencing of the ISR master regulator ATF4 also phenocopied these effects, confirming ISR engagement as a critical mediator of cytotoxicity. Conversely, epigenetic silencing or siRNA-mediated knockdown of BMF conferred resistance to Everolimus, whereas histone deacetylase inhibition restored BMF expression and drug sensitivity. Combined treatment with Everolimus and Venetoclax elicited potent, ISR-dependent antitumor activity in vivo.

These findings provide insight into the links between mTORC1 and the ISR and furnish proof-of-concept evidence for mTORC1 inhibition and sustained ISR activation as a viable strategy to overcome Venetoclax resistance to in T-ALL. Expression of BMF, a key mediator of this process, could predict response to this combination therapy.

Read more on CCBIO’s website.