Abstract 1399: Passenger deletion vulnerability in glioblastoma

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common, aggressive and lethal primary brain tumor in humans. Despite aggressive therapy the median survival of GBM patients is approximately 15 months. Monoallelic loss of PTEN occurs in ~70% of GBM. Through experimental validation studies in patient-derived primary GBM cell lines, we discovered that the lipogenic gene SCD undergoes unintended co-deletion as a passenger to PTEN, resulting in hemizygous loss of SCD in a subset of GBM. Additional in silico, genetic and biochemical analysis lead to the identification of two distinct PTEN-deleted subgroups: one with hemizygous co-deletion of PTEN and SCD (hereafter SCD-expressing), and another with very little or no PTEN/SCD expression due to PTEN mutation/homozygous loss and epigenetic suppression of the remaining SCD allele (hereafter SCD-non-expressing). SCD is an integral membrane protein of the endoplasmic reticulum (ER), involved in mediating the rate-limiting step of unsaturated fatty acid biosynthesis. SCD catalyzes the desaturation of the saturated fatty acids stearic (C18:0) and palmitic acids (C16:0) to the monounsaturated fatty acids oleic (C18:1) and palmitoleic acids (C16:1), respectively. We showed that the SCD-expressing lines are highly sensitive to SCD inhibition in the absence of dietary oleate and that the SCD-non-expressing lines are resistant to SCD inhibition. In vivo, we showed that mice treated with the SCD inhibitor survive longer than mice treated with vehicle. We also showed that SCD-expressing GBM lines acquire inhibitor resistance upon long-term exposure to the inhibitor in vitro. To understand the mechanism of resistance, we performed Reverse Phase Protein Array (RRPA) and RNA-Seq. Results illustrated the up-regulation of SCD among other genes. To identify the gene/s that provide SCD inhibitor resistance, we are currently performing a targeted shRNA screen of the highly expressed genes that we determined through RPPA and RNA-Seq. Citation Format: Nicole Oatman, Kakajan Komurov, Priyanka Arora, Pankaj Desai, Nupur Dasgupta, Kwangmin Choi, Biplab Dasgupta. Passenger deletion vulnerability in glioblastoma [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 1399.