Recurrent tumors that are resistant to conventional chemotherapy are a major challenge of ovarian cancer treatment. A better understanding of the underlying molecular mechanisms of chemoresistance is critical for developing more effective targeted therapies for ovarian cancer. In this study, we analyzed the transcriptomic profiles of thirteen pairs of matching primary and recurrent ovarian cancers to identify genes that were upregulated in the recurrent tumors. Among these genes, we identified sortilin-related receptor 1 (SORL1) and its role in promoting carboplatin resistance through regulating the stability of epidermal growth factor receptor (EGFR) and fibroblast growth receptor 4 (FGFR4) using ovarian cancer models in vitro and in vivo. We further identified that an anti-SORL1 antibody inhibited the pro-tumor functions of SORL1. Our data showed that a selective inhibitor of FGFR4, FGF401, can improve the therapeutic efficacy of carboplatin in a xenograft mouse model of ovarian cancer. This study has demonstrated the therapeutic potential of targeting the SORL1/FGFR4 pathway to improve the chemoresponse of patients with recurrent and/or resistant ovarian cancer.
对常规化疗产生耐药性的复发性肿瘤是卵巢癌治疗面临的主要挑战。深入理解化疗耐药性的潜在分子机制对于开发更有效的卵巢癌靶向治疗至关重要。本研究通过分析十三对匹配的原发性与复发性卵巢癌组织的转录组谱，识别出在复发性肿瘤中表达上调的基因。在这些基因中，我们利用体外和体内卵巢癌模型，确定了分拣蛋白相关受体1（SORL1）及其通过调节表皮生长因子受体（EGFR）和成纤维细胞生长因子受体4（FGFR4）稳定性促进卡铂耐药的作用机制。进一步研究发现，抗SORL1抗体能够抑制SORL1的促肿瘤功能。实验数据显示，选择性FGFR4抑制剂FGF401在卵巢癌异种移植小鼠模型中可增强卡铂的治疗效果。本研究证实了靶向SORL1/FGFR4通路在改善复发性及/或耐药性卵巢癌患者化疗反应方面具有治疗潜力。
SORL1-Mediated EGFR and FGFR4 Regulation Enhances Chemoresistance in Ovarian Cancer
肿瘤(癌症)患者之家