CBMT-05. GENETIC AND EPIGENETIC MECHANISMS REGULATING SCD INHIBITOR SENSITIVITY IN GLIOBLASTOMA. (11th November 2019)

• Record Type: Journal Article
• Authors: Oatman, Nicole; Dasgupta, Nupur; Dasgupta, Biplab; Choi, Kwangmin; Gawali, Mruniya; Gupta, Nishtha; Parameswaran, Sreeja; Lawler, Sean; Brennan, Cameron; Wu, Jianqiang; Sallans, Larry; Desai, Pankaj; Weirauch, Matthew; Komurov, Kakajan; Dasgupta, Biplab
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 6
• Page Start: vi33
• Page End: vi33
• Publication Date: 2019-11-11
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz175.127
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: A status-quo in targeted cancer therapy is that out of the thousands of somatic alterations found in a cancer cell, alterations only in driver genes determine therapeutic strategy. Despite unimpressive results of some driver-targeted therapies, and given that the majority of genomic alterations in cancer are not 'drivers', but 'passengers' / bystander alterations, it remains underappreciated whether targeting built-in vulnerabilities imposed by passenger gene alterations may provide therapeutic value. The tumor suppressor PTEN undergoes widespread functional inactivation including deletion in human cancer. PTEN deletion occurs frequently in GBM, sometimes as part of the 10q loss or chromosome 10 monosomy. We discovered that several genes including Stearoyl Co-A Desaturase, SCD (10q24.31), located 12 MB telomeric to PTEN is frequently co-deleted hemizygously and unintentionally in PTEN-deleted cancers. Strikingly, in a subset of GBM, SCD was also epigenetically silenced. A combination of SCD deletion and methylation resulted in two molecular subgroups – one that expressed SCD, and another that showed little or no detectable SCD. SCD, is an integral membrane protein of the endoplasmic reticulum and converts saturated fatty acids to monounsaturated fatty acids (Oleic and palmitoleic acids) that are critical for membrane fluidity and function, and thus SCD is generally overexpressed in most cancers. We show that SCD expressing lines are highly sensitive to multiple SCD inhibitors, while non-expressors are resistant. Despite modest BBB penetration, one SCD inhibitor was remarkably efficient in blocking intracranial tumor growth. SCD is an oxygen-dependent enzyme. We show that SCD retains significant enzymatic activity even in highly hypoxic conditions. Finally, through RNAseq, functional proteomics and ATACseq, we demonstrate an evolutionarily conserved mechanism of acquired resistance to SCD inhibitor through drug-induced acute phase signaling response in multiple SCD expressing cancers.