Metabolic perturbations sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics
Veerle W Daniels1,2, Jason J Zoeller2,3, Nick van Gastel4,5,6
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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.
Insights
Targeting cancer cell metabolism with NAMPT inhibitors sensitizes triple-negative breast cancer (TNBC) to BH3 mimetics. This approach exploits tumor-specific metabolic vulnerabilities, reducing tumor growth by depleting adenine and priming cells for apoptosis.
Area of Science:
- Biochemistry
- Cancer Biology
- Pharmacology
Background:
- Cancer cells exhibit distinct metabolic needs compared to normal cells, yet few metabolism-targeting drugs reach clinical success.
- Triple-negative breast cancer (TNBC) presents unique metabolic vulnerabilities that can be exploited for therapeutic benefit.
Purpose of the Study:
- To identify metabolic vulnerabilities in TNBC that enhance mitochondrial apoptotic priming and sensitivity to BH3 mimetics.
- To investigate the efficacy of targeting nicotinamide phosphoribosyltransferase (NAMPT) in combination with BH3 mimetics for TNBC treatment.
Main Methods:
- High-throughput dynamic BH3 profiling (HT-DBP) was employed to screen metabolism-perturbing small molecules.
- The effects of NAMPT inhibitors on apoptotic priming, BCL-2 family dependencies, and NAD+ concentrations were assessed in TNBC cells.
- Combination therapy (NAMPT inhibitor FK866 and MCL-1 antagonist S63845) was evaluated in a TNBC patient-derived xenograft model.
Main Results:
- NAMPT inhibitors were identified as promising candidates, increasing apoptotic priming and sensitizing TNBC cells to BH3 mimetics.
- NAMPT inhibition led to dependencies on specific antiapoptotic BCL-2 family members in TNBC cells.
- Combined FK866 and S63845 treatment significantly reduced tumor growth in vivo.
- NAMPT inhibition reduced NAD+ levels, causing adenine depletion and priming cells for apoptosis.
Conclusions:
- Exploiting the metabolic vulnerability of NAMPT in TNBC sensitizes cancer cells to BH3 mimetics.
- A combination strategy targeting NAMPT and MCL-1 shows therapeutic potential for TNBC.
- Metabolic and mitochondrial apoptotic signaling pathways are closely interconnected, offering novel therapeutic targets.
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