ADSS2 inhibition re-sensitizes acute myeloid leukemia to venetoclax and MCL1 inhibitors by suppressing mitophagy.

Resistance to targeted therapies remains a significant challenge in treating acute myeloid leukemia (AML). While BH3 mimetics, such as venetoclax (a BCL2 inhibitor), have shown promise, many patients develop resistance, particularly those with TP53 mutations. The precise mechanisms underlying this resistance, especially concerning metabolic pathways, are not fully understood. De novo purine synthesis is known to be crucial for tumor proliferation, but its direct impact on therapeutic resistance in AML, and specifically its interaction with BH3 mimetics, represents a critical knowledge gap that this research aims to address.

Researchers employed a dynamic BH3-priming-based CRISPR screen to identify genes whose deletion re-sensitizes drug-resistant acute myeloid leukemia cells to BH3 mimetics. They focused on ADSS2, an enzyme critical for adenosine monophosphate (AMP) synthesis. The study also utilized single-cell sequencing analysis on patient-derived xenograft samples to correlate ADSS2 activity with venetoclax responsiveness. An ADSS2 antagonist was developed and tested for its synergistic effects with BH3 mimetics in preclinical models, assessing apoptosis as a primary endpoint.

Deletion of ADSS2 significantly re-sensitized drug-resistant acute myeloid leukemia cells to both venetoclax and a myeloid cell leukemia-1 (MCL1) inhibitor. Single-cell sequencing of patient-derived xenograft samples revealed a positive association between high ADSS2 activity in TP53-mutant cells and poor responsiveness to venetoclax. This suggests ADSS2 activity is a predictive biomarker for resistance. > An ADSS2 antagonist was developed, which synergized with BH3 mimetics to promote apoptosis in preclinical models, indicating a potent combination strategy. Mechanistically, ADSS2 targeting-mediated sensitization correlated with downregulated AMP-activated protein kinase (AMPK) activity. In resistant cells, AMPK promotes mitophagy, a process that eliminates damaged mitochondria after BH3 mimetic treatment, thereby contributing to survival.