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

共 50 条

[31] Genome-Wide CRISPR Screen Identifies KEAP1 Perturbation as a Vulnerability of ARID1A-Deficient Cells
Fournier, Louis-Alexandre
Kalantari, Forouh
Wells, James P.
Lee, Joon Seon
Trigo-Gonzalez, Genny
Moksa, Michelle M.
Smith, Theodore
White, Justin
Shanks, Alynn
Wang, Siyun L.
Su, Edmund
Wang, Yemin
Huntsman, David G.
Hirst, Martin
Stirling, Peter C.
CANCERS, 2024, 16 (17)
[32] A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer
Ware, Kathryn E.
Thomas, Beatrice C.
Olawuni, Pelumi
Sheth, Maya U.
Hawkey, Nathan
Yeshwanth, M.
Miller, Brian C.
Vietor, Katherine J.
Jolly, Mohit Kumar
Kim, So Young
Armstrong, Andrew J.
Somarelli, Jason A.
CANCER RESEARCH, 2023, 83 (11)
[33] A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer
Ware, Kathryn E.
Thomas, Beatrice C.
Olawuni, Pelumi D.
Sheth, Maya U.
Hawkey, Nathan
Yeshwanth, M.
Miller, Brian C.
Vietor, Katherine J.
Jolly, Mohit Kumar
Kim, So Young
Armstrong, Andrew J.
Somarelli, Jason A.
FRONTIERS IN MOLECULAR BIOSCIENCES, 2023, 10
[34] MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition
Mollaoglu, Gurkan
Guthrie, Matthew R.
Boehm, Stefanie
Braegelmann, Johannes
Can, Ismail
Ballieu, Paul M.
Marx, Annika
George, Julie
Heinen, Christine
Chalishazar, Milind D.
Cheng, Haixia
Ireland, Abbie S.
Denning, Kendall E.
Mukhopadhyay, Anandaroop
Vahrenkamp, Jeffery M.
Berrett, Kristofer C.
Mosbruger, Timothy L.
Wang, Jun
Kohan, Jessica L.
Salama, Mohamed E.
Witt, Benjamin L.
Peifer, Martin
Thomas, Roman K.
Gertz, Jason
Johnson, Jane E.
Gazdar, Adi F.
Wechsler-Reya, Robert J.
Sos, Martin L.
Oliver, Trudy G.
CANCER CELL, 2017, 31 (02) : 270 - 285
[35] Chemical Genetics Screen Identifies COPB2 Tool Compounds That Alters ER Stress Response and Induces RTK Dysregulation in Lung Cancer Cells
Saraon, Punit
Snider, Jamie
Schormann, Wiebke
Rai, Ankit
Radulovich, Nikolina
Sanchez-Osuna, Maria
Coulombe-Huntington, Jasmin
Huard, Caroline
Mohammed, Mohammed
Lima-Fernandes, Evelyne
Theriault, Brigitte
Halabelian, Levon
Chan, Manuel
Joshi, Dhananjay
Drecun, Luka
Yao, Zhong
Pathmanathan, Shivanthy
Wong, Victoria
Lyakisheva, Anna
Aboualizadeh, Farzaneh
Niu, Li
Li, Fengling
Kiyota, Taira
Subramanian, Ratheesh
Joseph, Babu
Aman, Ahmed
Prakesch, Michael
Isaac, Methvin
Mamai, Ahmed
Poda, Gennady
Vedadi, Masoud
Marcellus, Richard
Uehling, David
Leighl, Natasha
Sacher, Adrian
Samarzija, Miroslav
Jakopovic, Marko
Arrowsmith, Cheryl
Tyers, Mike
Tsao, Ming-Sound
Andrews, David
Al-awar, Rima
Stagljar, Igor
JOURNAL OF MOLECULAR BIOLOGY, 2021, 433 (23)
[36] A Yeast-Based Chemical Screen Identifies a PDE Inhibitor That Elevates Steroidogenesis in Mouse Leydig Cells via PDE8 and PDE4 Inhibition
Demirbas, Didem
Wyman, Arlene R.
Shimizu-Albergine, Masami
Cakici, Ozgur
Beavo, Joseph A.
Hoffman, Charles S.
PLOS ONE, 2013, 8 (08):
[37] Small-Molecule Screen Identifies&IT De Novo&IT Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3
Herrera, Karina N. Gonzalez
Zaganjor, Elma
Ishikawa, Yoshinori
Spinelli, Jessica B.
Yoon, Haejin
Lin, Jia-Ren
Satterstrom, F. Kyle
Ringel, Alison
Mulei, Stacy
Souza, Amanda
Gorham, Joshua M.
Benson, Craig C.
Seidman, Jonathan G.
Sorger, Peter K.
Clish, Clary B.
Haigis, Marcia C.
CELL REPORTS, 2018, 22 (08): : 1945 - 1955
[38] A synthetic lethal screen identifies the Vitamin D receptor as a novel gemcitabine sensitizer in pancreatic cancer cells
Bhattacharjee, V.
Zhou, Y.
Yen, T. J.
CELL CYCLE, 2014, 13 (24) : 3839 - 3856
[39] Synthetic lethal CRISPR screen identifies a cancer cell-intrinsic role of PD-L1 in regulation of vulnerability to ferroptosis
Feng, Yang-Ying-Fan
Li, Yi-Cun
Liu, Hai-Ming
Xu, Rui
Liu, Yu-Tong
Zhang, Wei
Yang, Hong-Yu
Chen, Gang
CELL REPORTS, 2024, 43 (07):
[40] A novel high throughput screen identifies senescence-inducing activity of diaziquone in prostate cancer cells
Ewald, J.
Almassi, N.
Desotelle, J. A.
Laurilae, T. A. J.
Jarrard, D. F.
BJU INTERNATIONAL, 2007, 100 : 24 - 24

← 1 2 3 4 5 →