The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy is the first-line therapy for ER+/Her2- breast cancer, however, the development of drug resistance limited the efficacy of the agents. Although activation of the IFN signaling pathway has been identified as a critical driver of intrinsic and acquired CDK4/6i resistance, it remains unknown how the IFN signaling pathway was activated in resistant cells. Here, we report that NSRP1, a regulator of alternative mRNA splicing is downregulated in CDK4/6i resistant breast cancer cells and contributes to CDK4/6i resistance by mediating alternative splicing of NSD2 mRNA and activation of the IFN signaling pathway. Knockdown of NSRP1 reduces CDK4/6i (palbociclib) sensitivity of MCF7 cells while overexpression of NSRP1 sensitizes MCF7-PalR cells towards palbociclib treatment. Mechanistically, RNA sequencing suggests that NSRP1 knockdown strongly activates the IFN signaling pathway in MCF7 cells and elevates the expression of most of the "IFN-related palbociclib-resistance Signature" (IRPS) genes. NSRP1 also regulates numerous alternative splicing (AS) events in breast cancer cells, several of which are key regulators of the IFN signaling pathway. Among them, the inclusion of NSD2 exon 2 is elevated upon NSRP1 knockdown. Our data further show that the inclusion of NSD2 exon 2 is increased in breast cancer and associated with the poor prognosis of patients. In addition, including NSD2 exon 2 elevates NSD2 protein expression to activate the IFN signaling pathway. This study unveils the critical role of NSRP1 in regulating the IFN signaling pathway and the CDK4/6i resistance, which could be a promising biomarker for predicting therapy response.

中文翻译：

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剪接调节因子 NSRP1 的下调通过激活乳腺癌中的干扰素信号传导赋予对 CDK4/6 抑制剂的耐药性。


CDK4/6 抑制剂 （CDK4/6i） 联合内分泌治疗是 ER+/Her2- 乳腺癌的一线治疗，然而，耐药性的发展限制了药物的疗效。尽管 IFN 信号通路的激活已被确定为内源性和获得性 CDK4/6i 耐药的关键驱动因素，但 IFN 信号通路如何在耐药细胞中被激活仍未知。在这里，我们报道了 NSRP1 是一种选择性 mRNA 剪接调节因子，在 CDK4/6i 耐药乳腺癌细胞中下调，并通过介导 NSD2 mRNA 的选择性剪接和 IFN 信号通路的激活导致 CDK4/6i 耐药。NSRP1 的敲除降低了 MCF7 细胞的 CDK4/6i （palbociclib） 敏感性，而 NSRP1 的过表达使 MCF7-PalR 细胞对 palbociclib 治疗敏感。从机制上讲，RNA 测序表明 NSRP1 敲低强烈激活 MCF7 细胞中的 IFN 信号通路，并提高了大多数“IFN 相关 palbociclib 耐药特征”（IRPS） 基因的表达。NSRP1 还调节乳腺癌细胞中的许多选择性剪接 （AS） 事件，其中一些是 IFN 信号通路的关键调节因子。其中，NSD2 外显子 2 的包含在 NSRP1 敲低后升高。我们的数据进一步表明，NSD2 外显子 2 的包含在乳腺癌中增加，并且与患者的不良预后相关。此外，包括 NSD2 外显子 2 可提高 NSD2 蛋白表达以激活 IFN 信号通路。本研究揭示了 NSRP1 在调节 IFN 信号通路和 CDK4/6i 耐药性中的关键作用，这可能是预测治疗反应的有前途的生物标志物。