Abstract 7597: Therapeutic potential of ketogenic diet as an adjuvant to lenvatinib treatment in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) has been a major public health concern worldwide for decades because of its high mortality rates and poor prognosis, which are attributable to frequent tumor relapse and limited treatment regimens. Lenvatinib is one of the tyrosine kinase inhibitors approved for first-line treatment of advanced HCC, but its efficacy remains modest. Growing evidence suggest that the unsatisfactory survival benefits of lenvatinib could be attributed to the acquired drug resistance developed in HCC patients. In this study, we aim to explore the intrinsic metabolic vulnerability which could be exploited to enhance the treatment efficacy of lenvatinib in HCC. Our previous study showed that loss of tyrosine catabolism accompanied with a reduced downstream ketone metabolite beta-hydroxybutyrate (BHB) supports HCC initiation. To explore the therapeutic value of BHB in potentiating lenvatinib treatment in HCC, tyrosine catabolism-suppressing HCC cells were treated with BHB. We found that BHB treatment suppressed cell proliferation, increased cellular reactive oxygen species and potentiated the efficacy of lenvatinib treatment. Similar tumor-suppressive effect was observed when BHB was administered in vivo in mice bearing HCC patient derived xenograft. Combination treatment of lenvatinib and ketogenic diet which induces BHB level could drastically attenuate tumor development in immunocompetent mice bearing hepatic tumors. This study presents a potentially translatable combination treatment regimen to potentiate the therapeutic efficacy of lenvatinib in advanced HCC. Citation Format: Minghe Zhang, Terence Kin-Wah Lee, Stephanie Ma, Man Tong. Therapeutic potential of ketogenic diet as an adjuvant to lenvatinib treatment 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 7597.