(700.2) Reversal chemotherapeutic resistance of triple-negative breast cancer via functionally inhibiting RNA-binding protein HuR

Poster Board Number: B133

Lanjing Wei (The University of Kansas), Qi Zhang (The University of Kansas), Cuncong Zhong (The University of Kansas), Jeffrey Aubé (The University of North Carolina, Chapel Hill), Danny Welch (The University of Kansas Medical Center), Xiaoqing Wu (The University of Kansas), Liang Xu (The University of Kansas)

Chemotherapy remains the primary option for the systemic treatment of triple-negative breast cancer (TNBC). However, chemoresistance frequently occurs with the conventional use of chemotherapeutic drugs, resulting in a poorer prognosis and a higher recurrence rate of TNBC than other subtypes of breast cancer. Therefore, overcoming chemoresistance is a critical challenge to conquer for the successful treatment of TNBC. The RNA-binding protein Hu antigen R (HuR) is a posttranscriptional regulator. It can stabilize mRNA by binding to U- or AU-rich elements (ARE) mainly in 3’ untranslated region (UTR) of mRNA and therefore upregulate the translation most of the time. The encoded proteins of HuR target mRNAs are implicated in multiple cancer hallmarks, including therapeutic resistance. The cytoplasmic accumulation of HuR is reported to contribute to chemoresistance in several types of cancer cells, and HuR inhibition sensitizes cells to chemodrugs. We hypothesize that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of target mRNA 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 investigate the roles HuR played in the chemoresistance of TNBC and evaluate whether HuR inhibition by KH-3 can enhances the chemotherapy efficacy. To determine whether HuR inhibition overcomes acquired chemoresistance of TNBC, two MDA-MB-231 cell sub-lines resistant to docetaxel (231-TR) or doxorubicin (231-DR) were generated. Compared to the parental cell line, two sub-lines exhibit similar sensitivity to KH-3, and KH-3 re-sensitizes chemoresistant cells to docetaxel or doxorubicin in the MTT-based cytotoxicity assay and the colony formation assay, indicating that HuR inhibition can overcome the acquired chemoresistance. The combination index suggests that the combination of KH-3 with docetaxel or doxorubicin has a synergistic effect. The in vivo efficacy studies in both MDA-MB-231 and 231-TR orthotopic xenograft mouse models confirm that KH-3 synergizes docetaxel treatment. Mechanistically, several HuR direct target mRNAs implicated in chemoresistance were found upregulated in the resistant cells, which were reversed by KH-3 treatment. The detailed molecular mechanisms of how KH-3 sensitized TNBC cells to chemodrugs are being investigated. This research suggests that HuR inhibition is a promising strategy for overcoming chemoresistance in TNBC.

This work is supported in part by Susan G. Komen CCR18548252, R01 CA191785, BCRP BC151845, and KBA.