XBP1s Mediates Cross‐resistance to Combination Treatment of CDK4/6 Inhibitors plus Endocrine Therapy in Breast Cancer

Elevated spliced form of X‐box–binding protein 1 (XBP1) correlates with unfavorable responses to endocrine therapy plus CDK4/6 inhibitors in HR+/HER2− advanced breast cancer. XBP1s facilitates cell proliferation and G1/S transition by transcriptionally activating SND1, thereby activating the E2F1 pathway. By blocking XBP1 splicing, 4µ8C sensitizes cells and exhibits a synergistic effect with fulvestrant and palbociclib, providing a novel therapeutic strategy. Abstract CDK4/6 inhibitors combined with endocrine therapy is the standard treatment for patients with hormone receptor‐positive (HR+)/human epidermal growth factor receptor 2‐negative (HER2−) metastatic breast cancer (MBC). However, the inevitable development of treatment resistance and lack of approved biomarkers for predicting therapeutic efficacy remain urgent concerns. This study indicates that XBP1 is prominently and specifically expressed in HR+/HER2− breast cancer, and correlated with unfavorable response and poor progression‐free survival in patients with MBC receiving the combined therapy. XBP1s, a transcriptionally active spliced form of XBP1, accelerates tumor progression by facilitating cell proliferation and G1/S transition, and attenuates the efficacy of palbociclib and fulvestrant. Conversely, it can be reversed through epigenetic and pharmacological inhibition of XBP1s expression. Mechanistically, XBP1s activates the E2F1 pathway and upregulates downstream targets by transcriptionally activating SND1. Using patient‐derived organoids, it is confirmed that XBP1s plays a pro‐survival role and counteracts E2F1 pathway inhibition caused by the combined therapy, whereas 4µ8C sensitizes cells and exerts a synergistic effect with both fulvestrant and palbociclib. In conclusion, the findings indicate that XBP1s may serve as a potential marker for identifying patients who may not benefit from the medication, and offer a novel therapeutic strategy for patients with HR+/HER2− MBC. Elevated spliced form of X-box–binding protein 1 (XBP1) correlates with unfavorable responses to endocrine therapy plus CDK4/6 inhibitors in HR+/HER2− advanced breast cancer. XBP1s facilitates cell proliferation and G1/S transition by transcriptionally activating SND1, thereby activating the E2F1 pathway. By blocking XBP1 splicing, 4µ8C sensitizes cells and exhibits a synergistic effect with fulvestrant and palbociclib, providing a novel therapeutic strategy. Abstract CDK4/6 inhibitors combined with endocrine therapy is the standard treatment for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). However, the inevitable development of treatment resistance and lack of approved biomarkers for predicting therapeutic efficacy remain urgent concerns. This study indicates that XBP1 is prominently and specifically expressed in HR+/HER2− breast cancer, and correlated with unfavorable response and poor progression-free survival in patients with MBC receiving the combined therapy. XBP1s, a transcriptionally active spliced form of XBP1, accelerates tumor progression by facilitating cell proliferation and G1/S transition, and attenuates the efficacy of palbociclib and fulvestrant. Conversely, it can be reversed through epigenetic and pharmacological inhibition of XBP1s expression. Mechanistically, XBP1s activates the E2F1 pathway and upregulates downstream targets by transcriptionally activating SND1. Using patient-derived organoids, it is confirmed that XBP1s plays a pro-survival role and counteracts E2F1 pathway inhibition caused by the combined therapy, whereas 4µ8C sensitizes cells and exerts a synergistic effect with both fulvestrant and palbociclib. In conclusion, the findings indicate that XBP1s may serve as a potential marker for identifying patients who may not benefit from the medication, and offer a novel therapeutic strategy for patients with HR+/HER2− MBC. Advanced Science, Volume 12, Issue 44, November 27, 2025.