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

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, Rohini Narayanaswamy, Sung Choe, Yue Chen, Stefan Gross, Giovanni Cianchetta, Anil K. Padyana, Stuart Murray, Wei Liu, Kevin M. Marks, Joshua Murtie, Marion Dorsch, Shengfang Jin, Nelamangala Nagaraja, Scott A. Biller, Thomas Roddy, Janeta Popovici-Muller and Gromoslaw A. Smolen ()
Additional contact information
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
Gromoslaw A. Smolen: Agios Pharmaceuticals

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07959-4

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