Venetoclax resistance in acute lymphoblastic leukemia is characterized by increased mitochondrial activity and can be overcome by co-targeting oxidative phosphorylation.
Enzenmüller et al. explore why B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells sometimes resist the BCL-2 inhibitor Venetoclax (VEN), and how this resistance might be overcome. Although VEN is effective in several lymphoid cancers, resistance, either acquired during treatment or present from the start, remains a major challenge in BCP-ALL. To investigate this, the researchers developed VEN-resistant BCP-ALL cell lines and studied them using RNA sequencing and metabolic profiling. They found that gene signatures linked to the citric acid (TCA) cycle and respiratory electron transport chain were significantly enriched in resistant cells, indicating that these cells reprogram their metabolism toward enhanced mitochondrial respiration. Structurally, these resistant cells harbored more mitochondrial DNA and exhibited markedly larger and more elongated mitochondria. Seeking a strategy to counter this resistance, the team co-treated resistant cells with Oligomycin, an inhibitor of mitochondrial ATP synthase (complex V/ATPase). The combination induced apoptosis in both VEN-resistant cell lines and PDX samples, suggesting a potent synthetic-synergy by co-targeting BCL-2 and oxidative phosphorylation (OxPhos). Overall, the study reveals that VEN-resistance in BCP-ALL is associated with a metabolic shift to enhanced mitochondrial activity, and that co-inhibiting oxidative phosphorylation, alongside BCL-2, can restore apoptotic sensitivity. These findings strongly support further preclinical and possibly clinical evaluation of such combination regimens in VEN-resistant BCP-ALL.
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