Jiang Ziyan, Bi Fangfang, Ge Zhiping, Mansolf Miranda, Hartwich Tobias M P, Kolesnyk Viktoriia, Yang Kevin, Park Wonmin, Kim Dongin, Grechukhina Olga, Hui Pei, Kim Sang Wun, Yang-Hartwich Yang
The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06520, USA.
Cancers (Basel). 2025 Jan 13;17(2):244. doi: 10.3390/cancers17020244.
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.
对传统化疗耐药的复发性肿瘤是卵巢癌治疗的一大挑战。更好地理解化疗耐药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。在本研究中，我们分析了13对匹配的原发性和复发性卵巢癌的转录组图谱，以鉴定在复发性肿瘤中上调的基因。在这些基因中，我们利用体外和体内卵巢癌模型鉴定了sortilin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）的稳定性来促进卡铂耐药的作用。我们进一步发现，一种抗SORL1抗体可抑制SORL1的促肿瘤功能。我们的数据表明，FGFR4的选择性抑制剂FGF401可提高卡铂在卵巢癌异种移植小鼠模型中的治疗效果。本研究证明了靶向SORL1/FGFR4通路以改善复发性和/或耐药性卵巢癌患者化疗反应的治疗潜力。
