2. Academic Validation
  3. Metabolic perturbations sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics

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

  • Sci Signal. 2021 Jun 8;14(686):eabc7405. doi: 10.1126/scisignal.abc7405.
Veerle W Daniels 1 2,  Jason J Zoeller 2 3,  Nick van Gastel 4 5 6,  Kelley E McQueeney 1,  Salma Parvin 1,  Danielle S Potter 1,  Geoffrey G Fell 1,  Vinícius G Ferreira 1 7 8,  Binyam Yilma 1,  Rajat Gupta 1,  Johan Spetz 9,  Patrick D Bhola 1,  Jennifer E Endress 2 3,  Isaac S Harris 2 3 10,  Emanuel Carrilho 7 8,  Kristopher A Sarosiek 9,  David T Scadden 4 5 6,  Joan S Brugge 2 3,  Anthony Letai 11 2
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2 Ludwig Center at Harvard, Boston, MA 02215, USA.
  • 3 Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
  • 4 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • 5 Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
  • 6 Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 7 Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, SP 13568-250, Brazil.
  • 8 Instituto Nacional de Ciência e Tecnologia de Bioanalítica, INCTBio, Campinas, SP 13083-970, Brazil.
  • 9 Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02215, USA.
  • 10 Department of Biomedical Genetics and Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.
  • 11 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. anthony_letai@dfci.harvard.edu.
PMID: 34103421 DOI: 10.1126/scisignal.abc7405
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.

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