IDDF2022-ABS-0084 Adar1-mediated RNA editing of scd1 links lipid metabolism to drug resistance and self-renewal in gastric cancer. (2nd September 2022)

• Record Type: Journal Article
• Authors: Loh, Jia-Jian; Wong, Tin-Lok; Lu, Shixun; Yan, Helen HN; Siu, Hoi-Cheong; Chan, Dessy; Kam, Max JF; Lei, Zhou; Tong, Man; Copland, John A; Chan, Leilei; Xi, Ren; Yun, Jing-Ping; Leung, Suet-Yi
• Is Part Of: Gut. Volume 71(2022)Supplement 2
• Page Start: A45
• Page End: A45
• Publication Date: 2022-09-02
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2022-IDDF.47
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: The emergence of chemoresistance to 5-fluorouracil and cisplatin (5FU+CDDP) combination treatment curtailed long-term clinical benefits in gastric cancer (GC) patients. However, the targetable drivers governing 5FU+CDDP resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Methods: 5FU+CDDP resistant GC patient-derived organoid lines representative of the intestinal subtype were established. Comparative analyses using whole-exome sequencing (WES-seq) coupled with RNA-sequencing (RNA-seq) were performed. Clinical relevance, functional significance and mechanistic consequences were examined in GC organoid cultures and GC organoid xenografts. Results: JAK/STAT signaling and its downstream adenosine deaminases acting on RNA 1 (ADAR1) are shown to be concomitantly upregulated in the resistant lines. Functional characterization demonstrated that ADAR1 confers chemoresistance and self-renewal in an RNA-dependent manner. WES-seq coupled with RNA-seq identified enrichment of hyperedited lipid metabolism genes in resistant compared to parental lines. ADAR1-mediated A-to-I editing on 3'UTR of stearoyl-CoA desaturase (SCD1) increased binding of the KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting stability of SCD1 expression. Consequently, SCD1 endows chemoresistance by facilitating lipid droplet formation to alleviate ER stress; and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogated 5FU+CDDP chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score corresponds to a worse prognosis and predicts response to 5FU- and/or platinum-based chemotherapy. Conclusions: We demonstrate that chemoresistance can be derived from an aberrant lipid metabolism driven by alterations in RNA editing and identified an actionable target to circumvent chemoresistance in GC.