抑制脂肪酸氧化可克服胰腺癌获得性耐药：一项II期试验已启动

Purpose: Irinotecan treatment in pancreatic ductal adenocarcinoma (PDAC) induces acquired resistance through autophagy. Autophagy enhances fatty acid oxidation (FAO). Increased FAO activates the mTOR pathway via elevated ATP levels, thereby paradoxically co-activating mTOR and autophagy, the fundamental mechanisms underlying acquired drug resistance (ADR). The purpose of this study is to identify the role of FAO in anticancer drug ADR and to test whether suppressing FAO alongside anticancer drugs can overcome ADR. Experimental Design: We tested whether ADR could be reversed by blocking FAO in a pancreatic cancer xenograft model using either FAO gene knockdown or KN510713 (FAO inhibitors of KN510 and KN713 that target the carnitine acylcarnitine carrier and acetyl-CoA acyltransferase, respectively) in combination with irinotecan. In the Phase 1 trial, patients were enrolled in a dose-escalation cohort that received KN510713 alone. Results: When cancer cells are treated with anticancer drugs, they initially survive via pAMPK-dependent autophagy, but subsequently, as pAMPK is inactivated, they survive via pJNK-dependent autophagy. Autophagy induces FAO, thereby activating mTOR via increased ATP levels. In the PDAC xenograft model, co-administration of KN510713 with irinotecan abolished autophagy and mTOR activation, effectively overcoming ADR. Under this condition, the accumulation of fatty acids impairs autophagy flux via increased ROS, ultimately leading to cell death. In a Phase 1 clinical trial involving 12 patients with advanced solid tumors, KN510/KN713 demonstrated excellent tolerability and safety up to a maximum dose of 120/120 mg/day. No patients experienced a DLT during the study evaluation period. Five of the 12 patients (41.7%) achieved stable disease (SD) as the best response. Conclusion: FAO is essential for ADR via autophagy in cancer cells. Preclinical studies have shown that combining anticancer drugs with FAO inhibitors, such as KN510713, can overcome ADR. A Phase 1 trial has been completed, demonstrating safety. A Phase 2 trial has begun to evaluate the anticancer efficacy of FOLFIRINOX in combination with KN510713 in PDAC. Funding source: Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT, to SK (NRF-2019M3A9G1104345). The research was also supported by a grant from the National Cancer Center of Korea to WC (NCC 2410891-2) and by a clinical trial fund from New Cancer Cure-Bio Co., Korea.