Acquired drug resistance with autophagy is suppressed by fatty acid oxidation inhibition in pancreatic ductal adenocarcinoma

Purpose: We found that irinotecan treatment of pancreatic ductal adenocarcinoma (PDAC) induces autophagy. Autophagy enhances fatty acid oxidation (FAO), resulting in increased ATP production. Elevated ATP levels subsequently are linked to mTOR activation. As a result, prolonged chemotherapy paradoxically co-activates mTOR and autophagy, which are two pathways traditionally known to suppress each other, resulting in the promotion of acquired drug resistance. Experimental Design: To test whether blocking FAO reverses the acquired drug resistance, inhibition of FAO achieved by dual knockdown of carnitine-acylcarnitine carrier and acetyl-CoA acyltransferase 1 or inhibited the targets by KN510 and KN713. Anti-cancer effect was examined by xenograft model using human pancreatic cancer cells. Synergy of KN510 and KN713 with chemotherapeutic drugs also tested using a xenograft model. Results: We found that a combination treatment of KN510 and KN713 accompanied with irinotecan abolished autophagy activation and suppressed mTOR, resulting absence of drug resistance. In a PDAC xenograft model, combination treatment with irinotecan and the FAO inhibitor KN510713 significantly decreased acquired resistance, whereas irinotecan alone led to tumor regrowth. Conclusion: These findings highlight that the FAO pathway is a key mechanism of cancer-specific autophagy, supporting its role in the development of acquired drug resistance during chemotherapy. 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) and was supported by a grant from the National Cancer Center of Korea to WC (NCC 2410891-2).