Mitochondrial fatty acid oxidation as the target for blocking therapy-resistance and inhibiting tumor recurrence: The proof-of-principle model demonstrated for ovarian cancer cells.

INTRODUCTION: Cancer patients treated with current chemotherapeutic and targeted therapies frequently achieve partial remission, which ultimately relapse with more aggressive, drug-resistant tumor phenotypes. To a certain extent, drug-tolerant persister (DTP) cells are responsible for residual tumors after systemic anticancer therapy and the onset of acquired drug resistance. Therefore, novel therapies targeting DTP cells to prevent drug resistance and tumor recurrence are urgently needed. OBJECTIVES: We aimed to investigate the traits and key vulnerabilities of drug-tolerant ovarian cancer persister cells and to seek out potential therapeutic strategies. METHODS: We constructed paclitaxel-tolerant ovarian cancer persister cells by exposing ovarian cancer parental cells to a lethal dose of paclitaxel. Proteomics analysis, in vitro and in vivo assays were performed to identify biological processes that could serve as potential vulnerabilities in persister cells. RESULTS: Paclitaxel-tolerant ovarian cancer persister cells were found to undergo a metabolic reprogramming through the upregulation of fatty acid oxidation (FAO). Treatment with the FAO inhibitor ST1326 suppressed FAO and increased sensitivity to paclitaxel in persister cells. Moreover, combination therapy with paclitaxel and ST1326 prevented ovarian tumor recurrence with satisfactory biosafety in a mouse model of ovarian cancer relapse, indicating that FAO disruption can improve the efficacy of paclitaxel-based therapy in ovarian cancer. Mechanistically, we found that paclitaxel treatment upregulated CEBPB, a transcription factor that induced the expression of the FAO-related enzyme HADHA and contributed to FAO elevation in persister cells. CONCLUSIONS: This study revealed an upregulation of FAO in paclitaxel-tolerant ovarian cancer persister cells and provided a prospective paclitaxel-ST1326 combination therapy targeting persister cells that may prevent the development of acquired drug resistance and achieve superior long-term ovarian cancer control in the future. Our research established a conceptual framework for advancing personalized treatment approaches and enhancing patient outcomes in ovarian cancer therapy.