SORL1-Mediated EGFR and FGFR4 Regulation Enhances Chemoresistance in Ovarian Cancer.

Simple Summary: Treatment resistant recurrent disease is the main cause of death in patients diagnosed with ovarian cancer. The aim of this study is to better understand the mechanisms of chemoresistance, which can be targeted to improve therapeutic efficacy of current therapies in ovarian cancer. We identified SORL1 as a gene promoting drug resistance in recurrent ovarian cancer. We demonstrated the molecular mechanism by which SORL1 enhances cancer cell proliferation and platinum resistance through stabilizing the receptors of several growth factors. Therapeutic agents targeting SORL1 and its related pathways have potential to overcome the platinum resistance of recurrent ovarian cancer. 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. [ABSTRACT FROM AUTHOR]