Abstract 1697: Chemotherapy combined with fatty acid oxidation inhibition completely regressed tumor growth in a pancreatic cancer model

Abstract Purpose: We found that most ATP production in cancer cells depends on fatty acid oxidation (FAO). Most chemotherapeutic reagents including FOLFIRINOX regimen targeted anabolic metabolism of cancer cells such as DNA replication. All synthesis mechanisms require ATP for chemical reactions. Therefore, we proposed that blocking FAO together with chemotherapeutics may synergize anti-cancer effect by suppressing cancer growth metabolism. 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 was selected for CAC inhibition, and KN713 was selected for ACAA1 inhibition. To achieve maximum anti-cancer effect of FAO inhibition, KN510 and KN713 were combined for the treatment as KN510713. Anti-cancer effect was examined by xenograft model using human pancreatic cancer cells. Synergy of KN510713 with chemotherapeutic drugs also tested using a xenograft model. Results: Chemotherapy combined with KN510713 showed synergistic anti-cancer effect on 11 cancer types in in vitro analysis. Furthermore, xenograft pancreatic cancer showed completely suppressed effect of KN510713 treated with chemotherapeutics such as irinotecan only or FOLFIRINOX regimen. Conclusion: FAO inhibition stopped tumor growth by ATP depletion in pancreatic cancer. The changes in molecular signaling upon FAO inhibition revealed that ATP levels are a key regulator of all signaling. This suggests that whatever the signaling induced by the growth receptor, ATP down-regulation through FAO inhibition may provide a novel therapeutic effect. Thus, combinations of chemotherapeutic agents with FAO inhibitors have shown excellent anti-cancer activity in mice. Citation Format: Sang Myung Woo, Chae Young Kim, Woojin Ham, Joon Hee Kang, Mingyu Kang, Woosol Hong, Jeong Hwan Park, Wonyoung Choi, Soo Youl Kim. Chemotherapy combined with fatty acid oxidation inhibition completely regressed tumor growth in a pancreatic 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 1697.