Abstract 6663: DGAT1 inhibition enhances radiosensitivity in treatment-resistant cervical tumor cells

Abstract Standard of care treatment for locally advanced cervical cancer has proven to be minimally effective in one third of patients, emphasizing the need for new treatment strategies. Previous research has found that the supplementation with unsaturated free fatty acids may improve tumor response to radiation therapy. Building on this finding, this study investigates if radiation resistant cervical cancers are dependent upon fatty acid metabolism activation of the PI3K pathway. The P13K pathway is responsible for promoting cellular growth, survival and metastasis, thus mutations in this pathway can predict radio-sensitization through the inhibition of DGAT1. DGAT1 is an enzyme involved in cancer cell proliferation and spread by promoting fatty acid metabolism and energy storage, therefore its inhibition can lead to severe oxidative stress, killing cervical cancer cells. This study investigated the role of DGAT1 inhibition in enhancing radiosensitivity in cervical cancer cells using SiHa parental and SiHa PTEN-null cell lines. Cells were treated with the DGAT1 inhibitors Fenofibrate and A-922500, individually and in combination with radiation therapy (RT). Alamar Blue assays measured cell viability post-treatment, while Western blotting evaluated DGAT1 protein expression following radiation exposure and inhibitor treatment. Flow cytometry was used to quantify apoptosis and reactive oxygen species (ROS), including total, lipid, and mitochondrial ROS, across different treatment conditions. Additionally, colony-forming assays assessed the long-term impact of treatments on cell proliferation and survival. Results showed that radiation upregulated DGAT1 expression, likely as a protective response to oxidative stress, and that inhibiting DGAT1 significantly decreased cell viability and increased apoptosis when combined with radiation, particularly in PTEN-null cells. These findings suggest that targeting DGAT1 disrupts lipid metabolism and enhances radiosensitivity in cervical cancer cells. DGAT1 plays a critical role in protecting cervical cancer cells from oxidative damage and maintaining lipid homeostasis during radiation therapy. Inhibition of DGAT1 using Fenofibrate and A-922500 successfully sensitized both SiHa parental and SiHa PTEN-null cells to radiation, with a more pronounced effect observed in the PTEN-null cell line, which is associated with PI3K pathway activation and radio-resistance. These results highlight the therapeutic potential of targeting DGAT1 to overcome radio-resistance in cervical cancer, particularly in tumors with PI3K/Akt pathway activation. Future directions include testing DGAT1 inhibitors in other radioresistant cervical cancer models and conducting in vivo studies to further explore the clinical potential of this approach. Citation Format: Leahan E. Castillo, Marin Guthrie, Naoshad Muhammad, Naomi Msengi, Julie Schwarz. DGAT1 inhibition enhances radiosensitivity in treatment-resistant cervical tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6663.