Abstract 1413: Targeting the RNA-binding protein HuR to overcome chemoresistance in triple-negative breast cancer

Abstract

Abstract Patients with triple-negative breast cancer (TNBC) have a lower 5-year relative survival rate (77%) than overall for breast cancer (91%). Chemotherapy remains the primary choice for the systemic treatment of TNBC. However, patients frequently develop resistance to conventional chemotherapy, resulting in poorer prognosis and higher recurrence than other subtypes of breast cancer. Therefore, overcoming chemotherapy resistance is critical for the successful treatment of TNBC. The RNA-binding protein Hu antigen R (HuR) plays an important role in chemotherapy resistance. 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 mRNA and upregulate their translation. The encoded proteins are implicated in multiple cancer hallmarks, including chemoresistance. The overexpression of HuR, especially accumulated cytoplasmic expression, is related to chemoresistance in many types of cancer. We hypothesize that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of mRNA and thus reduce the translation of proteins responsible for chemoresistance.Recently, our lab reported a small molecule HuR inhibitor, KH-3, which potently inhibits HuR function by disrupting the HuR-mRNA interactions. KH-3 effectively suppresses growth and invasion of TNBC cells in vitro and in vivo. In this study, we assessed whether HuR is a target for overcoming chemoresistance and evaluated whether KH-3, as a small molecule HuR functional inhibitor, could enhance the efficacy of chemotherapy for TNBC cells. To determine whether HuR inhibition overcomes acquired chemoresistance of TNBC, we generated cell sublines derived from human MDA-MB-231 with acquired resistance against docetaxel or doxorubicin. KH-3 could synergize TNBC cells to chemotherapy in vitro and in vivo. Interestingly, KH-3 treatment could re-sensitize chemoresistant TNBC cells to drugs, indicating that HuR inhibition can overcome acquired chemoresistance. Regarding mechanisms of action, several pathways and HuR direct target mRNA are implicated in docetaxel and doxorubicin resistance, but detailed molecular mechanisms are still under investigation. This study provides a new strategy to overcome chemotherapy resistance and improve the survival of TNBC. Citation Format: Lanjing Wei, Qi Zhang, 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 American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1413.