Abstract 3074: Sorafenib resistance and cholesterol metabolism in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is among the most prevalent cancers and a leading cause of cancer-related deaths worldwide. Sorafenib, a multikinase inhibitor, serves as a key first-line treatment for HCC when surgical intervention is not an option. However, primary and acquired resistance to sorafenib has significantly limited its effectiveness, reducing the disease control rate. Dysregulation of numerous genes that influence cancer cell proliferation, survival, and drug resistance contributes to this challenge. Identifying the molecular drivers of sorafenib resistance remains critical to improving treatment outcomes. Several factors, including activation of oncogenic pathways (e.g., Akt/mTOR), hypoxia, cholesterol metabolism, multidrug resistance, and autophagy, play pivotal roles in driving resistance. RNA/DNA binding proteins, such as Y-box binding protein 1 (YBX1), are central to cancer progression, metastasis, and drug resistance. Elevated YBX1 expression correlates with poor prognosis in HCC. Our preliminary data indicate that YBX1 overexpression enhances oncogenic phenotypes such as proliferation, migration, and colony formation. Additionally, it upregulates oncogenic markers like CD44, PDL1, SNAIL, and TWIST, further promoting HCC progression. Conversely, YBX1 inhibition increases sensitivity to sorafenib, as evidenced by the downregulation of drug resistance markers in HCC cell lines. Kinases also play a critical role in drug resistance, and activation of Akt/mTOR-associated genes was observed in YBX1 overexpression models. Moreover, cholesterol metabolism pathways appear to be significantly impacted by YBX1. Specifically, sterol regulatory element-binding transcription factors (SREBF1 and SREBF2) and downstream lipid metabolism genes, such as COL1A1, are positively correlated with YBX1 expression and are activated in HepG2 and Huh7 sorafenib-resistant cells. Notably, YBX1 knockdown reversed the effects of SREBF2-associated lipid metabolism genes, reducing their role in drug resistance. Collectively, these findings suggest that YBX1 contributes to sorafenib resistance in HCC through cholesterol metabolism and oncogenic signaling. This research highlights YBX1 as a potential therapeutic target, with the promise of sensitizing sorafenib-resistant HCC cells and improving treatment outcomes. Citation Format: Veerababu Nagati, Dennis Kwabiah, Yamile Abuchard Anaya, Manish K. Tripathi. Sorafenib resistance and cholesterol metabolism in hepatocellular carcinoma [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 3074.