Abstract 3504: A chemical biology screen identifies a unique vulnerability of neuroendocrine cancer cells to SQLE inhibition

Abstract

Abstract Numerous reports have described the differential metabolism of cancer cells as compared to their normal counterparts. However, only relatively few metabolic genes with cancer-specific mutations have been reported and the identification of cancer subsets with particular metabolic vulnerabilities remains a challenge. To explore potential cancer-specific dependencies, we conducted a chemical biology screen utilizing a collection of small molecule inhibitors targeting diverse metabolic pathways in a large panel of cancer cell lines. A subset of neuroendocrine tumors, particularly small cell lung cancers (SCLC), displayed a striking dependence on squalene epoxygenase, SQLE, an enzyme in the cholesterol biosynthetic pathway. To develop further confidence in these findings, we have determined the first three-dimensional SQLE structure and further advanced a pharmacological toolbox for SQLE. Using these tools, we showed that the observed effects are on target and that the patterns of cellular sensitivity observed in vitro display excellent translation to in vivo xenografts studies. Interestingly, using a variety of orthogonal approaches, we demonstrated that SQLE sensitivity appears not to be related to overall inhibition of the cholesterol pathway but rather to specific and toxic accumulation of the SQLE substrate, squalene. Collectively, these findings highlight the utility of chemical biology screens and identify SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly SCLC. Citation Format: Christopher Mahoney, David Pirman, Victor Chubukov, Taryn Sleger, Anil Padyana, Stefan Gross, Sebastian Hayes, Zi Peng Fan, Gabrielle McDonald, Yu Chen, Joshua Murtie, Giovanni Cianchetta, Raj Nagaraja, Rohini Narayanaswamy, Sung Choe, Stuart Murray, Shengfang Jin, Scott Biller, Thomas Roddy, Gromoslaw A. Smolen. A chemical biology screen identifies a unique vulnerability of neuroendocrine cancer cells to SQLE inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3504.