Metabolic perturbations sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics

Blocking adenine synthesis sensitizes some triple-negative breast cancer cells to apoptotic death. Depleting adenine to prime for apoptosis Triple-negative breast cancers (TNBCs) are notoriously difficult to treat. Daniels et al. identified a metabolic vulnerability in TNBC patient cells and cell lines that may create a therapeutic opportunity in patients. The authors searched for metabolism-perturbing small-molecule compounds that sensitized TNBC lines to apoptosis induced by BH3 mimetics that block antiapoptotic proteins. They found that inhibition of NAMPT, the rate-limiting enzyme of the NAD+ salvage pathway, and specifically the loss of adenine downstream of NAMPT inhibition primed TNBC cells for apoptotic death. The findings suggest that combining NAMPT inhibitors with BH3 mimetics might be effective in some patients with TNBC. Cancer cells have differential metabolic dependencies compared to their nonmalignant counterparts. However, few metabolism-targeting compounds have been successful in clinical trials. Here, we investigated the metabolic vulnerabilities of triple-negative breast cancer (TNBC), particularly those metabolic perturbations that increased mitochondrial apoptotic priming and sensitivity to BH3 mimetics (drugs that antagonize antiapoptotic proteins). We used high-throughput dynamic BH3 profiling (HT-DBP) to screen a library of metabolism-perturbing small molecules, which revealed inhibitors of the enzyme nicotinamide phosphoribosyltransferase (NAMPT) as top candidates. In some TNBC cells but not in nonmalignant cells, NAMPT inhibitors increased overall apoptotic priming and induced dependencies on specific antiapoptotic BCL-2 family members. Treatment of TNBC cells with NAMPT inhibitors sensitized them to subsequent treatment with BH3 mimetics. The combination of a NAMPT inhibitor (FK866) and an MCL-1 antagonist (S63845) reduced tumor growth in a TNBC patient–derived xenograft model in vivo. We found that NAMPT inhibition reduced NAD+ concentrations below a critical threshold that resulted in depletion of adenine, which was the metabolic trigger that primed TNBC cells for apoptosis. These findings demonstrate a close interaction between metabolic and mitochondrial apoptotic signaling pathways and reveal that exploitation of a tumor-specific metabolic vulnerability can sensitize some TNBC to BH3 mimetics.