Abstract 4772: Stearoyl-CoA Desaturase (SCD1) regulates liver tumor initiating cells through modulating ER stress

Abstract

Abstract Sorafenib is the FDA approved drug for patients with advanced hepatocellular carcinoma (HCC), but the survival benefit is only modest, partly due to drug resistance. Increasing evidence shows that tumor-initiating cells (T-ICs) are intrinsically resistant to conventional treatments, and targeting signaling pathways in T-ICs provides potential therapeutic targets for HCC. In our established enriched T-IC population, we identified the activation of a lipogenesis pathway in which expression of stearoyl-CoA desaturase-1 (SCD1), an enzyme involved in the conversion of saturated into monounsaturated fatty acids, was most significant. SCD1 overexpression is frequently found in HCC samples and is significantly associated with poorer patient survival. Using overexpression and knockdown approaches, SCD1 was found to regulate the traits of T-ICs, including tumorigenicity, self-renewal, differentiation, drug resistance and the expression of liver T-IC markers. Interestingly, SCD1 was markedly upregulated in our established sorafenib-resistant cell lines as well as patient-derived xenografts (PDTXs), and its overexpression predicts the clinical response of HCC patients to sorafenib treatment. Consistently, pharmacological inhibition of SCD1 suppressed T-IC phenotypes and enhanced sensitivity to sorafenib treatment. Using a patient-derived xenograft model, we found that a novel SCD1 inhibitor (SSI-4) in combination with sorafenib demonstrated a maximal tumor suppressive effect. Induction of endoplasmic reticulum (ER) stress-mediated T-IC differentiation can account for the enhanced sensitivity towards sorafenib treatment upon SCD1 suppression. In conclusion, SCD1-induced ER stress may specifically increase the sensitivity of liver T-ICs to the effects of sorafenib treatment. Targeting SCD1 in combination with sorafenib therapy may be a novel therapeutic regimen against HCC. Citation Format: Kin Fai Ma, Eunice Yuen Ting Lau, Irene Oi Lin Ng, Kin Wah Lee. Stearoyl-CoA Desaturase (SCD1) regulates liver tumor initiating cells through modulating ER stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4772. doi:10.1158/1538-7445.AM2017-4772