Mechanisms of stearoyl CoA desaturase inhibitor sensitivity and acquired resistance in cancer
| Autor: | Kakajan Komurov, Brian Gebelein, Larry Sallans, Priyanka Arora, Jianqiang Wu, Matthew T. Weirauch, Frank B. Furnari, Sean E. Lawler, Nishtha Gupta, Angelo D'Alessandro, Gary A. Gudelsky, Biplab Dasgupta, Joseph Salomone, Kwangmin Choi, Nicole Oatman, Nupur Dasgupta, Sreeja Parameswaran, Cameron Brennan, Mruniya V. Gawali, Julie A. Reisz, Pankaj B. Desai |
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| Rok vydání: | 2021 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Mice 03 medical and health sciences 0302 clinical medicine Neoplasms hemic and lymphatic diseases medicine Animals Humans Tensin PTEN Health and Medicine cardiovascular diseases Epigenetics Research Articles Cancer 030304 developmental biology 0303 health sciences Multidisciplinary biology Lipogenesis SciAdv r-articles Lipid metabolism Cell Biology Lipid Metabolism medicine.disease Stearoyl-CoA Desaturase Drug Resistance Neoplasm 030220 oncology & carcinogenesis DNA methylation Cancer research biology.protein Proto-Oncogene Proteins c-fos Research Article FOSB |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.abd7459 |
| Popis: | Genetic and epigenetic mechanisms determine SCD inhibitor sensitivity and acquired resistance through FOSB in cancer. 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. |
| Databáze: | OpenAIRE |
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