Bortezomib Restores Venetoclax Sensitivity in Acute Myeloid Leukemia Cell Lines with Intrinsic and Acquired Resistance

Abstract Venetoclax (VEN), a selective BCL-2 inhibitor, effectively induces apoptosis in a wide range of malignancies. VEN-based regimens, which combine VEN with either hypomethylating agents or low-dose cytarabine, have markedly improved treatment outcomes in elderly patients with acute myeloid leukemia (AML). However, approximately one third of patients exhibit intrinsic resistance to these regimens, and the majority of initial responders eventually develop acquired resistance. Therefore, intrinsic and acquired resistance to VEN-based regimens remains a major barrier to achieving durable clinical responses in patients with AML. In this study, we aimed to identify effective treatment strategies to overcome VEN resistance. Among the drugs tested in this study, we found that bortezomib (BTZ), a proteasome inhibitor, showed potent synergy with VEN in inducing apoptosis in a wide range of AML cell lines, irrespective of RAS or TP53 mutation status. Mechanistically, BTZ upregulates proapoptotic proteins such as NOXA, BIM, and PUMA, which neutralize MCL1 and promote apoptosis. Notably, NOXA upregulation plays a critical role in the efficacy of the combination of VEN and BTZ. Moreover, BTZ resensitized AML cell lines with acquired resistance to VEN, further supporting its role in overcoming therapeutic resistance. Importantly, the combination of BTZ and VEN significantly prolongs the survival of mice inoculated with a VEN-resistant AML cell line harboring BAX mutations, which are commonly observed in relapsed AML following VEN-based regimens and confer resistance to VEN by inhibiting the BAX-dependent apoptotic pathway. Collectively, this study provides a rationale for the VEN–BTZ combination as a potential strategy to overcome VEN resistance in certain AML subsets.