Abstract PS16-20: Targeting the RNA-binding protein HuR to overcome chemoresistance in triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) has a much lower 5-year relative survival rate (77%) than the overall breast cancer (91%). Chemotherapy remains the primary choice for the treatment of TNBC. However, patients often develop resistance to conventional chemotherapy after long-term exposure to the chemo-drugs, resulting in poorer prognosis and higher tumor reoccurrence compared to other subtypes of breast cancer. Therefore, understanding and overcoming drug resistance is critical for the successful treatment of TNBC. The Hu antigen R (HuR) or ELAVL1 (embryonic lethal, abnormal vision, Drosophila-like protein 1) plays an important role in chemotherapy resistance. The RNA-binding protein HuR is a posttranscriptional regulator, which can stabilize target mRNAs by binding to U- or AU-rich elements (ARE) mainly in 3’ untranslated region (UTR) of mRNAs and upregulate the translation of them. The encoded proteins are implicated in multiple cancer hallmarks, including chemoresistance. The overexpression of HuR, especially accumulated cytoplasmic expression, has been identified to be related to chemoresistance in many types of cancer. We hypothesize that inhibition of HuR function by disrupting its interaction with mRNAs can accelerate the decay of mRNAs and thus reduce the translation of proteins responsible for chemoresistance.Recently, we reported a small molecule HuR inhibitor, KH-3, which potently inhibit HuR function by disrupting the HuR-mRNA interaction. KH-3 can effectively suppress the growth and invasion of TNBC cells in vitro and in vivo. In this study, we aim to verify that HuR is a target for overcoming chemoresistance and evaluate that KH-3 as a HuR functional inhibitor can enhance the efficacy of chemotherapy for TNBC cells. To determine whether HuR inhibition can overcome acquired chemotherapy resistance of TNBCs, we generated MDA-MB-231 sub-cell lines with acquired resistance against docetaxel or doxorubicin. Our results show that inhibition of HuR by KH-3 could synergize chemotherapy for TNBC in vitro and in vivo. More interestingly, KH-3 treatment could re-sensitize resistant TNBC cells to chemo-drugs, indicating that HuR inhibition can overcome acquired chemoresistance. In the study of mechanism of actions, several pathways and HuR direct target mRNAs are found to be involved in acquired docetaxel and doxorubicin resistance. The detailed molecular mechanisms of how KH-3 sensitizes TNBC to chemotherapy is currently under investigation. This study provides a new strategy to overcome chemotherapy resistance and improve the overall survival rate of patients with TNBC. Citation Format: Lanjing Wei, Qi Zhang, Gulhumay Gardashova, Cuncong Zhong, Jeffrey Aubé, Danny R. Welch, Xiaoqing Wu, Liang Xu. Targeting the RNA-binding protein HuR to overcome chemoresistance in triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-20.