Inhibiting Fatty Acid Oxidation Reverses Autophagy-Mediated Acquired Chemotherapy Resistance in Pancreatic Ductal Adenocarcinoma

In pancreatic ductal adenocarcinoma (PDAC), irinotecan (1μmol/L) chemotherapy triggers a dual-phase Autophagy process that drives drug resistance. Although mTOR and Autophagy exert suppressive effects on each Other, coactivation of mTOR and Autophagy has been observed when PDAC cells begin to regrow after treatment. Therefore, we hypothesized that the distinct temporal phases of Autophagy are governed by independent upstream pathways. Initially, DNA damage activated AMPK, inducing early Autophagy within 24 hours that fueled fatty acid oxidation (FAO), boosting ATP production. After 48 hours, elevated ATP levels inactivated AMPK and activated mTOR, which typically suppresses Autophagy. However, Autophagy and FAO activity persisted beyond 72 hours of irinotecan treatment via the JNK1-Beclin-1 pathway. This created a paradoxical state in which mTOR and Autophagy were coactivated, promoting cell survival under irinotecan treatment. Irinotecan combined with FAO inhibition using KN510713 (a combination of KN510 targeting the carnitine-acylcarnitine transporter and KN713 targeting acetyl-CoA acyltransferase1/2) or FAO gene knockdown blocked Autophagy flux and cell growth. FAO inhibition-induced fatty acid accumulation impaired Autophagy flux and induced cytotoxicity, leading to Cancer cell death. In xenograft models, combining irinotecan with KN510713 significantly prevented tumor regrowth compared with irinotecan alone. These findings suggest that targeting FAO induced by Autophagy activation may overcome acquired drug resistance in PDAC while minimizing the toxic side effects associated with systemic inhibition of Autophagy in healthy cells.

Significance: Combined treatment with irinotecan and fatty acid oxidation inhibition reverses acquired drug resistance driven by Autophagy in pancreatic Cancer.