Abstract 1544: Fatty acid oxidation inhibition with anti-cancer agents abrogated tumor growth in a melanoma cancer model

Abstract Purpose: We found that chemotherapy on melanoma induced fatty acid oxidation (FAO). Therefore, we propose that FAO inhibition may suppress tumor growth synergistically with anti-cancer therapeutics. Experimental Design: To block FAO, CAC (carnitine-acylcarnitine carrier, gene: SLC25A20) in the mitochondria inner membrane and ACAA1 (acetyl-CoA acyltransferase1, gene: ACAA1) in the peroxisome were targeted for inhibition. KN510 and KN713 were identified through drug screening for their inhibitory effects on CAC, and ACAA1, respectively. Using allograft and xenograft models with mouse and human melanoma cancer cells, we investigated the anti-cancer effects of KN510713 in combination with standard chemotherapy. Results: Anti-cancer drug treatment such as dabrafenib and dacarbazine induced fatty acid catabolism as well as mitochondrial oxidative phosphorylation for ATP production which is the core metabolic pathway for FAO. Increase of ATP production correlated with mTOR activation. Anti-cancer drug treatment combined with KN510713 induced cell death significantly concomitantly with mTOR inactivation in vitro. Melanoma cancer models of allograft and xenograft showed significant suppression of tumor growth by KN510713 treatment with anti-cancer agents such as dabrafenib or dacarbazine. Conclusion: FAO inhibition abrogated tumor growth by ATP depletion in melanoma. The changes in molecular signaling upon FAO inhibition revealed that ATP levels are a key regulator of all signaling. Thus, combinations of systemic anti-cancer agents with FAO inhibitors have shown excellent anti-cancer activity in mice. Even if signal transduction is induced by various growth receptors, ATP down-regulation through FAO inhibition may provide a novel therapeutic effect. Funding source: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT to SK (NRF-2019M3A9G1104345) and by a grant from the National Cancer Center of Korea to WC (NCC 2410891-1). Citation Format: Jeong Hwan Park, Wonyoung Choi, Woojin Ham, Woosol Hong, Chae-Young Kim, Ho Lee, Soo-Youl Kim. Fatty acid oxidation inhibition with anti-cancer agents abrogated tumor growth in a melanoma cancer model [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 1544.