Stabilization of the PP2A-B56α complex overcomes Venetoclax-Azacitidine resistance by impairing oxidative phosphorylation in AML

ABSTRACT: Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in acute myeloid leukemia (AML) patients. Drug-resistant cells exhibit an enhanced reliance on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need. We have recently demonstrated that the specific activation of the phosphatase PP2A-B56α enhances the pro-apoptotic efficacy of venetoclax in AML. Here, through leveraging unbiased multi-omics-based approaches, and using both genetic and pharmacological tools, we define key new roles for the tumor suppressor PP2A-B56α complex in OXPHOS regulation and treatment responses in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56α heterocomplex with the novel PP2A molecular glue, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza-sensitive and -resistant AML cell lines, primary cells, and in vivo models.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Goutham Narla 

PROVIDER: PXD062308 | JPOST Repository | Tue Oct 27 00:00:00 GMT 2026

REPOSITORIES: jPOST