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

• Published in: Nature communications 2019-01, Vol.10 (1), p.96-14, Article 96
• Main Authors: Mahoney, Christopher E., Pirman, David, Chubukov, Victor, Sleger, Taryn, Hayes, Sebastian, Fan, Zi Peng, Allen, Eric L., Chen, Ying, Huang, Lingling, Liu, Meina, Zhang, Yingjia, McDonald, Gabrielle, Narayanaswamy, Rohini, Choe, Sung, Chen, Yue, Gross, Stefan, Cianchetta, Giovanni, Padyana, Anil K., Murray, Stuart, Liu, Wei, Marks, Kevin M., Murtie, Joshua, Dorsch, Marion, Jin, Shengfang, Nagaraja, Nelamangala, Biller, Scott A., Roddy, Thomas, Popovici-Muller, Janeta, Smolen, Gromoslaw A.
• Format: Article
• Language: English
• Subjects: 49/98; 631/67/1612/2143; 631/67/2327; 631/92/287; 64/60; 96; 96/106; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biology; Biosynthesis; Cancer; Cell Line, Tumor; Cholesterol; Cholesterol - biosynthesis; Drug Delivery Systems; Drug Screening Assays, Antitumor; Gene Deletion; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Inhibition; Kinases; Lungs; Metabolism; multidisciplinary; Neuroendocrine tumors; Organic chemistry; Science; Science (multidisciplinary); Sensitivity; Squalene; Squalene epoxidase; Squalene Monooxygenase - antagonists & inhibitors; Squalene Monooxygenase - metabolism; Substrates; Therapeutic applications; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07959-4

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. Cancer cells are metabolically adaptable and the identification of specific vulnerabilities is challenging. Here the authors identify a subset of neuroendocrine cell lines exquisitely sensitive to inhibition of SQLE, an enzyme in the cholesterol biosynthetic pathway, due to the toxic accumulation of pathway intermediate squalene.