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A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition

Author

Listed:
  • Christopher E. Mahoney

    (Agios Pharmaceuticals)

  • David Pirman

    (Agios Pharmaceuticals)

  • Victor Chubukov

    (Agios Pharmaceuticals)

  • Taryn Sleger

    (Agios Pharmaceuticals)

  • Sebastian Hayes

    (Agios Pharmaceuticals)

  • Zi Peng Fan

    (Agios Pharmaceuticals)

  • Eric L. Allen

    (Agios Pharmaceuticals)

  • Ying Chen

    (Shanghai ChemPartner Co. Ltd.)

  • Lingling Huang

    (Shanghai ChemPartner Co. Ltd.)

  • Meina Liu

    (Shanghai ChemPartner Co. Ltd.)

  • Yingjia Zhang

    (Shanghai ChemPartner Co. Ltd.)

  • Gabrielle McDonald

    (Agios Pharmaceuticals)

  • Rohini Narayanaswamy

    (Agios Pharmaceuticals)

  • Sung Choe

    (Agios Pharmaceuticals)

  • Yue Chen

    (Agios Pharmaceuticals)

  • Stefan Gross

    (Agios Pharmaceuticals)

  • Giovanni Cianchetta

    (Agios Pharmaceuticals)

  • Anil K. Padyana

    (Agios Pharmaceuticals)

  • Stuart Murray

    (Agios Pharmaceuticals)

  • Wei Liu

    (Agios Pharmaceuticals)

  • Kevin M. Marks

    (Agios Pharmaceuticals)

  • Joshua Murtie

    (Agios Pharmaceuticals)

  • Marion Dorsch

    (Agios Pharmaceuticals)

  • Shengfang Jin

    (Agios Pharmaceuticals)

  • Nelamangala Nagaraja

    (Agios Pharmaceuticals)

  • Scott A. Biller

    (Agios Pharmaceuticals)

  • Thomas Roddy

    (Agios Pharmaceuticals)

  • Janeta Popovici-Muller

    (Agios Pharmaceuticals
    Decibel Therapeutics)

  • Gromoslaw A. Smolen

    (Agios Pharmaceuticals
    Celsius Therapeutics)

Abstract

Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers.

Suggested Citation

  • Christopher E. Mahoney & David Pirman & Victor Chubukov & Taryn Sleger & Sebastian Hayes & Zi Peng Fan & Eric L. Allen & Ying Chen & Lingling Huang & Meina Liu & Yingjia Zhang & Gabrielle McDonald & R, 2019. "A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07959-4
    DOI: 10.1038/s41467-018-07959-4
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