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

被引：64

作者：

Mahoney, Christopher E. ^{[1
]}

Pirman, David ^{[1
]}

Chubukov, Victor ^{[1
]}

Sleger, Taryn ^{[1
]}

Hayes, Sebastian ^{[1
]}

Fan, Zi Peng ^{[1
]}

Allen, Eric L. ^{[1
]}

Chen, Ying ^{[2
]}

Huang, Lingling ^{[2
]}

Liu, Meina ^{[2
]}

Zhang, Yingjia ^{[2
]}

McDonald, Gabrielle ^{[1
]}

Narayanaswamy, Rohini ^{[1
]}

Choe, Sung ^{[1
]}

Chen, Yue ^{[1
]}

Gross, Stefan ^{[1
]}

Cianchetta, Giovanni ^{[1
]}

Padyana, Anil K. ^{[1
]}

Murray, Stuart ^{[1
]}

Liu, Wei ^{[1
]}

Marks, Kevin M. ^{[1
]}

Murtie, Joshua ^{[1
]}

Dorsch, Marion ^{[1
]}

Jin, Shengfang ^{[1
]}

Nagaraja, Nelamangala ^{[1
]}

Biller, Scott A. ^{[1
]}

Roddy, Thomas ^{[1
]}

Popovici-Muller, Janeta ^{[1
,3
]}

Smolen, Gromoslaw A. ^{[1
,4
]}

机构：

[1] Agios Pharmaceut, 88 Sidney St, Cambridge, MA 02139 USA

[2] Shanghai ChemPartner Co Ltd, 998 Halei Rd, Shanghai 201203, Peoples R China

[3] Decibel Therapeut, 1325 Boylston St,Suite 500, Boston, MA 02215 USA

[4] Celsius Therapeut, 215 First St, Cambridge, MA 02142 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

SQUALENE EPOXIDASE; LUNG-CANCER; CHOLESTEROL; METABOLISM; SENSITIVITY; ONCOGENE; ASCL1; LEADS; D2O;

D O I：

10.1038/s41467-018-07959-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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