用 EC359 靶向 LIF/LIFR 信号可克服卵巢癌化疗耐药并增强化疗疗效

Background: Ovarian cancer (OCa) is the deadliest gynecologic malignancy, with nearly 90% of patients experiencing disease recurrence following standard treatments. Leukemia inhibitory factor (LIF) and its receptor (LIFR) are implicated in OCa progression, chemoresistance, and recurrence. The TCGA data indicated a negative correlation between the expression of LIFR and LIF and the survival of OCa. Elevated expressions of LIF and LIFR in recurrent OCa underscores the need for innovative therapeutic strategies targeting this pathway. In this study, we tested the hypothesis that the progression of OCa to therapy resistance is dependent on LIF/LIFR signaling and that the standard of care interventions will be enhanced by the disruption of LIF/LIFR signaling with the small molecule inhibitor EC359. Methods: The effectiveness of the LIFR inhibitor EC359, in combination with paclitaxel and/or carboplatin, was evaluated in both established and chemotherapy-resistant OCa cell lines, as well as in patient-derived xenograft (PDX) models. Paclitaxel-resistant cell lines were developed and characterized through RNA sequencing. To assess therapeutic impact, cell viability, colony formation, and apoptosis were measured using MTT assays, colony formation assays, and apoptosis assays, respectively. Mechanistic insights into the combination therapy were obtained via Western blot analysis to identify modulated signaling pathways. Additionally, 3D organoids derived from xenografts were employed to examine the ex vivo effects of EC359 combined with chemotherapy. The efficacy of the combination treatment was further validated in vivo using both CDX and PDX models. Results: Utilizing long term culture of OCa cells with increasing concentrations of chemotherapy, we have successfully established several chemotherapy-resistant OCa model cell lines. EC359 significantly enhanced the anti-tumor efficacy of chemotherapy in reducing cell viability and suppressing colony formation in clonogenicity assays. Further, EC359 treatment enhanced apoptosis in OCa cells by promoting ferroptosis pathway. Remarkably, the combination therapy demonstrated increased effectiveness of chemotherapy in paclitaxel-resistant and carboplatin-resistant OCa cells, underscoring its potential to overcome chemotherapy resistance. The results from the CDX model demonstrated the effectiveness of EC359 as a monotherapy for resistant OCa. Further, the results from PDX model studies demonstrated the efficacy of EC359 in conjunction with carboplatin and as a maintenance therapy for OCa. These findings suggest EC359 as a potent combination agent with chemotherapy for improved therapeutic outcomes in OCa. Conclusions: These findings provide compelling preclinical evidence that LIFR inhibition with EC359 is a promising strategy to enhance chemotherapy efficacy in OCa. Supported by NIH R01 CA266970.