Abstract 1988: Mass spectrometry profiling identifies ENO2 as a driver of lenvatinib resistance in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, and lenvatinib is a multi-kinase inhibitor approved by the FDA as a first-line drug for advanced HCC since 2018. Lenvatinib demonstrated antitumor activity with a higher objective response rate, longer progression-free survival, and time to progression in a non-inferiority trial compared with sorafenib. However, the clinical benefits of lenvatinib remain limited as acquired resistance to lenvatinib during HCC treatment is inevitable. This highlights the need to understand the molecular mechanisms of lenvatinib resistance and to explore new therapeutic approaches to overcome this resistance. Tumor lineage plasticity, a recognized hallmark of cancer, is a phenomenon in which tumor cells dedifferentiate into a more stemness state to attain cellular plasticity, enabling them to evade targeted therapeutic interventions. However, the mechanism by which cellular plasticity contributes to lenvatinib resistance remains elusive. In this study, we employed proteomic mass spectrometry to investigate altered proteins in two pairs of parental lenvatinib-sensitive and their corresponding trained lenvatinib-resistant HCC cell lines. This analysis revealed that upregulation of enolase 2 (ENO2), a glycolytic enzyme that catalyzes the dehydration and conversion of 2-phosphoglycerate to phosphoenolpyruvate, is a critical contributor. ENO2 upregulation is frequently observed in HCC and is strongly correlated with aggressive clinical features, including poor survival, advanced tumor stage, and poor differentiation status. We further showed that ENO2 upregulation in HCC is positively correlated with stemness and hepatic progenitor marker signatures, as well as hypoxia, and subsequently demonstrated that ENO2 is regulated by hypoxia/HIF-1α, with hypoxia response element sequences located in the ENO2 promoter region. Research is underway to investigate the functional role and underlying molecular mechanisms associated with ENO2-driven lenvatinib resistance and cellular plasticity in HCC. Citation Format: Sukbum Kim, Jia-Jian Loh, Huajian Yu, Ki-Fong Man, Kai-Yu Ng, Terence Kin-Wah Lee, Clive Yik-Sham Chung, Stephanie Ma. Mass spectrometry profiling identifies ENO2 as a driver of lenvatinib resistance in hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1988.