Inhibiting Fatty Acid Oxidation Suppresses Acquired Resistance to Standard Chemotherapy in Melanoma

Immunotherapy and RAF-targeted therapy have become standard treatments for melanoma, significantly improving outcomes compared to earlier therapies. When resistance to initial treatment develops, the older chemotherapy drug Dacarbazine is used. However, resistance to both therapies has emerged, promoting ongoing research to further enhance survival rates. Among various theories, autophagy is believed to play a critical role in acquired drug resistance, as increased autophagy has been observed in resistance to multiple anticancer agents. In this study, Dabrafenib was administered to melanoma cells with an RAF mutation, while Dacarbazine was given to cells with an Raf wild type. Both cell lines showed increased autophagy and FAO following treatment with the anticancer drugs. When FAO was blocked during drug treatment, melanoma cells became more susceptible to cell death. In xenograft models, B16F10 melanoma (Raf wild type) demonstrated regrowth due to acquired resistance after two weeks of Dacarbazine treatment. Conversely, a combination of Dacarbazine and the FAO inhibitors KN510 and KN713 (a combination of KN510 and KN713:KN510713) caused near-complete remission without regrowth. A375 melanoma (BRAF^V600E) developed resistance after four weeks of Dabrafenib treatment, yet the combination of Dabrafenib and KN510713 resulted in near-complete remission with no signs of regrowth. Based on these findings, combining FAO inhibitors with first-line therapies may be a promising approach for managing melanoma, regardless of RAF mutation status.