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

Venetoclax, a selective BCL-2 inhibitor, effectively induces apoptosis in a wide range of malignancies. Venetoclax-based regimens, combined venetoclax 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 venetoclax-based regimens remains a major barrier to achieving durable clinical responses in AML patients. In this study, we aimed to identify effective treatment strategies to overcome venetoclax resistance. Among drugs tested in this study, we found that bortezomib, a proteasome inhibitor, showed potent synergy with venetoclax in inducing apoptosis in a wide range of AML cell lines, irrespective of RAS or TP53 mutation status. Mechanistically, bortezomib upregulates pro-apoptotic 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 venetoclax and bortezomib. Moreover, bortezomib resensitized AML cell lines with acquired resistance to venetoclax, further supporting its role in overcoming therapeutic resistance. Importantly, the combination of bortezomib and venetoclax significantly prolongs the survival of mice inoculated with venetoclax-resistant AML cell line harboring BAX mutations, which are commonly observed in relapsed AML following venetoclax-based regimens and confer resistance to venetoclax by inhibiting BAX-dependent apoptotic pathway. Collectively, this study provides a rationale for venetoclax-bortezomib combination as a potential strategy to overcome venetoclax resistance in certain AML subsets.