Open AccessMechanisms of stearoyl CoA desaturase inhibitor sensitivity and acquired resistance in cancer
Author(s) -
Nicole Oatman,
Nupur Dasgupta,
Priyanka Arora,
Kwangmin Choi,
Mruniya V. Gawali,
Neeraj Gupta,
Sreeja Parameswaran,
Joseph Salomone,
Julie A. Reisz,
Sean Lawler,
Frank B. Furnari,
Cameron Brennan,
Jianqiang Wu,
Larry Sallans,
Gary A. Gudelsky,
Pankaj B. Desai,
Brian Gebelein,
Matthew T. Weirauch,
Angelo D’Alessandro,
Kakajan Komurov,
Biplab Dasgupta
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abd7459
Subject(s) - epigenetics , fosb , cancer , sensitivity (control systems) , cancer research , biology , medicine , genetics , bioinformatics , gene , gene expression , electronic engineering , engineering
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.