Chemotherapy remains the primary systemic treatment for triple-negative breast cancer (TNBC). However, patients with TNBC often develop resistance to conventional chemotherapy, resulting in a poorer prognosis and a higher recurrence rate than those with other subtypes of breast cancer. The RNA-binding protein Hu antigen R (HuR) is a posttranscriptional regulator, which can stabilize target mRNAs and regulate the translation of encoded proteins implicated in several hallmarks of cancer, including drug resistance. The high cytoplasmic expression of HuR is associated with high-grade malignancy and poor clinical outcomes of breast cancer. The accumulated cytoplasmic HuR has also been reported to contribute to chemoresistance in several types of cancer cells and inhibition of HuR sensitizes cancer cells to chemotherapy. Therefore, HuR is a promising target to overcome chemoresistance. We hypothesize that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of target mRNAs and thus reduce the translation level of proteins responsible for chemoresistance.Recently, our lab reported a small molecule HuR inhibitor, KH-3, which potently inhibits HuR function by disrupting HuR-mRNA interactions. In this study, we aim to investigate the functions of HuR in TNBC chemoresistance formation and evaluate whether HuR inhibition by KH-3 can enhance the efficacy of chemotherapy for TNBC. In order to determine whether HuR inhibition overcomes acquired chemoresistance of TNBC, we generated two MDA-MB-231 cell sub-lines with acquired resistance to docetaxel (231-TR) or doxorubicin (231-DR), respectively. Compared to the parental cell line, the two resistant sub-lines exhibit similar sensitivity to KH-3, and KH-3 re-sensitizes chemoresistant cells to docetaxel and doxorubicin in the MTT-based cytotoxicity assay and the colony formation assay, indicating that HuR inhibition can overcome acquired chemoresistance. The combination index suggests that the combination KH-3 with docetaxel or. doxorubicin has a synergistic effect. Moreover, the in vivo efficacy studies confirm that KH-3 synergized docetaxel treatment in both MDA-MB-231 and 231-TR orthotopic xenograft models. Mechanistically, several HuR direct target mRNAs implicated in chemoresistance are upregulated in the resistant cells, and KH-3 treatment can reverse the enhanced mRNA levels. The bioinformatic analysis suggests that several pathways may involve in the acquired resistance to docetaxel and doxorubicin. However, detailed molecular mechanisms of how KH-3 sensitizes TNBC to chemotherapy are still under investigation. This study suggests that inhibition of HuR is a promising strategy for overcoming chemotherapy resistance of TNBC.

Citation Format: Lanjing Wei, Qi Zhang, Cuncong Zhong, Jeffrey Aubé, Danny R. Welch, Xiaoqing Wu, Liang Xu. Overcome chemoresistance of triple-negative breast cancer by inhibiting the RNA-binding protein HuR [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-16.