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

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.

SUBMITTER: Mahoney CE

PROVIDER: S-EPMC6327044 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Mahoney Christopher E CE Pirman David D Chubukov Victor V Sleger Taryn T Hayes Sebastian S Fan Zi Peng ZP Allen Eric L EL Chen Ying Y Huang Lingling L Liu Meina M Zhang Yingjia Y McDonald Gabrielle G Narayanaswamy Rohini R Choe Sung S Chen Yue Y Gross Stefan S Cianchetta Giovanni G Padyana Anil K AK Murray Stuart S Liu Wei W Marks Kevin M KM Murtie Joshua J Dorsch Marion M Jin Shengfang S Nagaraja Nelamangala N Biller Scott A SA Roddy Thomas T Popovici-Muller Janeta J Smolen Gromoslaw A GA

Nature communications 20190109 1

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 cholestero ...[more]

PMID: 30626880

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Project description:BackgroundCurrent treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects.Methods and findingsIn this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression.ConclusionsTaken together, our results propose novel combinatorial approaches to inhibit prostate cancer cell growth. Disulfiram-sunitinib combination was identified as one of the potent synergistic approaches. Since sunitinib alone has been reported to lack efficacy in prostate cancer clinical trials, our results provide a rationale for novel combinatorial approach to target prostate cancer more efficiently.

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

Publications

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

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