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

Abstract

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.

Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics

“…Interestingly, this study showed that the observed acquired antiapoptotic dependence to the BRAF inhibitor dabrafenib was not mediated by an increase in MCL1 expression, but through a NOXA mRNA destabilization leading to protein decrease (151). Other novel therapeutic combinations with BH3 mimetics were recently identified using this approach in NSCLC (200), breast cancer (123,158,201,202), esophageal cancer/ mesothelioma (203), and pediatric cancers (146,204), among others. Depicting the complexity of these prosurvival adaptations and antiapoptotic cross-talk is key to accurately identifying the right drug combination and the optimal sequential administration to maximize the cytotoxic effect in tumors.…”

A Nicotinamide Phosphoribosyltransferase Inhibitor, FK866, Suppresses the Growth of Anaplastic Meningiomas and Inhibits Immune Checkpoint Expression by Regulating STAT1

“…once per day). The dose of the compound was determined based on previous studies ( 30 – 32 ). FK866 was suspended in 45% propylene glycol + 5% Tween 80 + double distilled H 2 O (ddH 2 O).…”

Synthetic Lethal Interaction with BCL-XL Blockade Deepens Response to Cetuximab in Patient-Derived Models of Metastatic Colorectal Cancer

“…Specifically, we measured the percentage of cytochrome c release from mitochondria after cell exposure to synthetic BH3 peptides (binding antiapoptotic molecules) in 10 PDXOs treated with vehicle or cetuximab for 24 hours. As previously reported for PDX-isolated cultures of triple-negative breast cancer (35), we considered a threshold difference of 10% in the magnitude of cytochrome c mobilization between drug-treated cells and untreated controls ("delta priming") as a biologically relevant indicator of apoptotic sensitization induced by therapy. Post-cetuximab delta priming was increased to near-or abovethreshold levels after exposure to the promiscuous Bmf-Y or BIM peptides in eight and five PDXOs, respectively; only one model (CRC0096) was poorly primed by cetuximab (Fig.…”