PRP4K is a HER2-regulated modifier of taxane sensitivity

ABSTRACTThe taxanes are used alone or in combination with anthracyclines or platinum drugs to treat breast and ovarian cancer, respectively. Taxanes target microtubules in cancer cells and modifiers of taxane sensitivity have been identified <i>in vitro</i>, including drug efflux and mitotic checkpoint proteins. Human epidermal growth factor receptor 2 (HER2/ERBB2) gene amplification is associated with benefit from taxane therapy in breast cancer yet high HER2 expression also correlates with poor survival in both breast and ovarian cancer. The pre-mRNA splicing factor 4 kinase PRP4K (PRPF4B), which we identified as a component of the U5 snRNP also plays a role in regulating the spindle assembly checkpoint (SAC) in response to microtubule-targeting drugs. In this study, we found a positive correlation between PRP4K expression and HER2 status in breast and ovarian cancer patient tumours, which we determined was a direct result of PRP4K regulation by HER2 signaling. Knock-down of PRP4K expression reduced the sensitivity of breast and ovarian cancer cell lines to taxanes, and low PRP4K levels correlated with in vitro-derived and patient acquired taxane resistance in breast and ovarian cancer. Patients with high-grade serous ovarian cancer and high HER2 levels had poor overall survival; however, better survival in the low HER2 patient subgroup treated with platinum/taxane-based therapy correlated positively with PRP4K expression (HR = 0.37 [95% CI 0.15–0.88]; p = 0.03). Thus, PRP4K functions as a HER2-regulated modifier of taxane sensitivity that may have prognostic value as a marker of better overall survival in taxane-treated ovarian cancer patients.

摘要：紫杉烷类药物可单药使用，或分别与蒽环类药物、铂类药物联合，用于治疗乳腺癌与卵巢癌。紫杉烷类药物的作用靶点为癌细胞内的微管，目前已在体外（in vitro）鉴定出多种调控紫杉烷敏感性的因子，包括药物外排蛋白与有丝分裂检验点蛋白。人表皮生长因子受体2（Human epidermal growth factor receptor 2，HER2/ERBB2）基因扩增与乳腺癌患者从紫杉烷治疗中获益相关，但HER2高表达同时与乳腺癌、卵巢癌患者的不良生存预后相关。我们将前mRNA剪接因子4激酶PRP4K（PRPF4B）鉴定为U5小核核糖核蛋白（U5 snRNP）的组分，该蛋白在应答微管靶向药物的过程中，可参与调控纺锤体组装检验点（spindle assembly checkpoint，SAC）。本研究中，我们在乳腺癌与卵巢癌患者的肿瘤组织中发现，PRP4K的表达水平与HER2状态呈正相关，且该相关性由HER2信号通路对PRP4K的直接调控所介导。敲低PRP4K的表达可降低乳腺癌与卵巢癌细胞系对紫杉烷类药物的敏感性；而PRP4K低表达与体外实验及乳腺癌、卵巢癌患者获得性紫杉烷耐药性相关。高HER2表达的高级别浆液性卵巢癌患者总体生存预后较差；然而，在接受铂类联合紫杉烷治疗的低HER2表达患者亚组中，PRP4K表达水平与更优的总体生存率呈正相关（风险比HR=0.37，95%置信区间CI：0.15~0.88；p=0.03）。综上，PRP4K作为受HER2调控的紫杉烷敏感性调控因子，有望成为接受紫杉烷治疗的卵巢癌患者总体生存预后良好的预测标志物。