Cargando…
A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition
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 inhib...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Publishing Group UK
2019
|
| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327044/ https://www.ncbi.nlm.nih.gov/pubmed/30626880 http://dx.doi.org/10.1038/s41467-018-07959-4 |
| _version_ | 1783386397757931520 |
|---|---|
| author | 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. |
| author_facet | 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. |
| author_sort | Mahoney, Christopher E. |
| collection | PubMed |
| description | 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. |
| format | Online Article Text |
| id | pubmed-6327044 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2019 |
| publisher | Nature Publishing Group UK |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-63270442019-03-28 A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition 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. Nat Commun Article 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. Nature Publishing Group UK 2019-01-09 /pmc/articles/PMC6327044/ /pubmed/30626880 http://dx.doi.org/10.1038/s41467-018-07959-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| spellingShingle | Article 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. A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition |
| title | A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition |
| title_full | A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition |
| title_fullStr | A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition |
| title_full_unstemmed | A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition |
| title_short | A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition |
| title_sort | chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to sqle inhibition |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327044/ https://www.ncbi.nlm.nih.gov/pubmed/30626880 http://dx.doi.org/10.1038/s41467-018-07959-4 |
| work_keys_str_mv | AT mahoneychristophere achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT pirmandavid achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT chubukovvictor achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT slegertaryn achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT hayessebastian achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT fanzipeng achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT allenericl achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT chenying achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT huanglingling achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT liumeina achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT zhangyingjia achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT mcdonaldgabrielle achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT narayanaswamyrohini achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT choesung achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT chenyue achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT grossstefan achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT cianchettagiovanni achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT padyanaanilk achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT murraystuart achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT liuwei achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT markskevinm achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT murtiejoshua achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT dorschmarion achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT jinshengfang achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT nagarajanelamangala achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT billerscotta achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT roddythomas achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT popovicimullerjaneta achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT smolengromoslawa achemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT mahoneychristophere chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT pirmandavid chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT chubukovvictor chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT slegertaryn chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT hayessebastian chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT fanzipeng chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT allenericl chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT chenying chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT huanglingling chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT liumeina chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT zhangyingjia chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT mcdonaldgabrielle chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT narayanaswamyrohini chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT choesung chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT chenyue chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT grossstefan chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT cianchettagiovanni chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT padyanaanilk chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT murraystuart chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT liuwei chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT markskevinm chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT murtiejoshua chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT dorschmarion chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT jinshengfang chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT nagarajanelamangala chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT billerscotta chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT roddythomas chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT popovicimullerjaneta chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition AT smolengromoslawa chemicalbiologyscreenidentifiesavulnerabilityofneuroendocrinecancercellstosqleinhibition |