IRE1α inhibitor enhances paclitaxel sensitivity of triple-negative breast cancer cells

PurposeBreast cancer is the most commonly diagnosed cancer in women, and triple-negative breast cancer (TNBC) accounts for approximately 15%-20% of all breast cancers. TNBC is highly invasive and malignant. Due to the lack of relevant receptor markers, the prognosis of TNBC is poor and the five-year survival rate is low. Paclitaxel is the first-line drug for the treatment of TNBC, which can inhibit cell mitosis. However, many patients develop drug resistance during treatment, leading to chemotherapy failure. Therefore, finding new therapeutic combinations to overcome TNBC drug resistance can provide new strategies for improving the survival rate of TNBC patients.MethodsCell viability assay, RT-qPCR, Colony formation assay, Western blot, and Xenogeneic transplantation methods were used to investigate roles and mechanisms of IRE1 alpha/XBP1s pathway in the paclitaxel-resistant TNBC cells, and combined paclitaxel and IRE1 alpha inhibitor in the treatment of TNBC was examined in vitro and in vivo.ResultsWe found activation of UPR in paclitaxel-resistant cells, confirming that IRE1 alpha/XBP1 promotes paclitaxel resistance in TNBC. In addition, we demonstrated that the combination of paclitaxel and IRE1 alpha inhibitors can synergistically inhibit the proliferation of TNBC tumors both in vitro and in vivo,suggesting that IRE1 alpha inhibitors combined with paclitaxel may be a new treatment option for TNBC.ConclusionsIn this study, we demonstrated the important role of IRE1 alpha signaling in mediating paclitaxel resistance and identified that combination therapies targeting IRE1 alpha signaling could overcome paclitaxel resistance and enhance chemotherapy efficacy.