Mechanisms of stearoyl CoA desaturase inhibitor sensitivity and acquired resistance in cancer Journal Article

Authors: Oatman, N.; Dasgupta, N.; Arora, P.; Choi, K.; Gawali, M. V.; Gupta, N.; Parameswaran, S.; Salomone, J.; Reisz, J. A.; Lawler, S.; Furnari, F.; Brennan, C.; Wu, J.; Sallans, L.; Gudelsky, G.; Desai, P.; Gebelein, B.; Weirauch, M. T.; D'Alessandro, A.; Komurov, K.; Dasgupta, B.
Article Title: Mechanisms of stearoyl CoA desaturase inhibitor sensitivity and acquired resistance in cancer
Abstract: The lipogenic enzyme stearoyl CoA desaturase (SCD) plays a key role in tumor lipid metabolism and membrane architecture. SCD is often up-regulated and a therapeutic target in cancer. Here, we report the unexpected finding that median expression of SCD is low in glioblastoma relative to normal brain due to hypermethylation and unintentional monoallelic co-deletion with phosphatase and tensin homolog (PTEN) in a subset of patients. Cell lines from this subset expressed undetectable SCD, yet retained residual SCD enzymatic activity. Unexpectedly, these lines evolved to survive independent of SCD through unknown mechanisms. Cell lines that escaped such genetic and epigenetic alterations expressed higher levels of SCD and were highly dependent on SCD for survival. Last, we identify that SCD-dependent lines acquire resistance through a previously unknown FBJ murine osteosarcoma viral oncogene homolog B (FOSB)-mediated mechanism. Accordingly, FOSB inhibition blunted acquired resistance and extended survival of tumor-bearing mice treated with SCD inhibitor. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
Keywords: cell culture; tumors; mammals; therapeutic targets; diseases; hypermethylation; viruses; acquired resistance; epigenetic alterations; stearoyl-coa desaturase; enzymatic activities; lipid metabolisms; lipogenic enzymes
Journal Title: Science Advances
Volume: 7
Issue: 7
ISSN: 2375-2548
Publisher: Amer Assoc Advancement Science  
Date Published: 2021-02-10
Start Page: eabd7459
Language: English
DOI: 10.1126/sciadv.abd7459
PROVIDER: scopus
PMCID: PMC7875532
PUBMED: 33568479
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
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MSK Authors
  1. Cameron Brennan
    206 Brennan