Abstract 4667: HDAC9 as a potential regulator of lenvatinib resistance in hepatocellular carcinoma

Abstract Lenvatinib is used as the first-line therapy for advanced hepatocellular carcinoma (HCC) patients. However, poor response and compromised therapeutic effect with prolonged treatment are frequently observed in HCC patients. To elucidate the underlying mechanisms, lenvatinib responsive and non-responsive stages were modeled in liver tumor-bearing immunocompetent mice which were divided into lenvatinib and vehicle control treatment groups. Tumor tissues after short and prolonged lenvatinib treatment were harvested for single-cell RNA sequencing. Results from single-cell RNA sequencing revealed heterogenous tumor cell sub-populations associated with tumor differentiation and identified an upregulated expression of class IIa histone acetylase HDAC9 in lenvatinib-treated tumor at the non-responsive stage. Upregulation of HDAC9 was similarly observed in lenvatinib-resistant human patient-derived xenograft (PDX). Functional studies suggested that suppressing HDAC9 could re-sensitize lenvatinib response in both in vitro and in vivo models. In sum, we identified a potential regulator of lenvatinib treatment response in HCC. Citation Format: Yunong Xie, Minghe Zhang, Yan Liu, Linglin Liu, Alfred Sze-Lok Cheng, Stephanie Ma, Man Tong. HDAC9 as a potential regulator 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 4667.