ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer

Abstract

Chemotherapy remains an integral component in the management of gastric cancer. Fluorouracil (5FU) and cisplatin (CDDP) doublet chemotherapy is often deployed to combat gastric cancer. However, many patients, particularly those with Lauren intestinal gastric cancer, who were initially responsive to chemotherapy eventually developed acquired chemoresistance, thus obstructing the long-term clinical benefits of chemotherapy. Despite extensive research, the molecular drivers governing 5FU+CDDP resistance remain elusive, partly due to the paucity of physiologically accurate models. To address this unmet clinical need, we establish 5FU+CDDP resistant intestinal subtype gastric cancer patient-derived organoid lines that faithfully mirror the patient’s physiological condition. These resistant organoids display blunted sensitivity to chemotherapy as well as potentiated self-renewal properties, a feature that could endow tumor recurrence. Comparative transcriptomic profiling reveals that IFN/JAK/STAT signaling and its downstream effector, adenosine deaminases acting on RNA 1 (ADAR1), are concomitantly upregulated in the resistant organoid lines. Functional characterization demonstrated that ADAR1 confers therapy resistance and self-renewal in an RNA editing-dependent manner. Whole-exome sequencing (WES) coupled with RNA-seq identifies an enrichment of hyper-edited lipid metabolism genes in the resistant organoid lines. Mechanistically, ADAR1-mediated A-to-I editing on the 3’UTR of stearoyl-CoA desaturase (SCD1) increases the binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby enhancing SCD1 mRNA stability and protein abundance. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced endoplasmic reticulum (ER) stress and augments self-renewal through increasing β-catenin stability. Of significance, pharmacological inhibition of SCD1 abrogates chemoresistance and reduces the self-renewal capacity. Clinically, high proteomic level of ADAR1 and SCD1, or high ADAR1 mRNA/SCD1 editing signature score predicts a worse prognosis in patients treated with chemotherapy. Taken together, our findings unveil a novel actionable target to circumvent 5FU+CDDP chemoresistance.