RANK expression and Luminal BC response to CDK4/6 inhibitors. RANK expression and Luminal BC response to CDK4/6 inhibitors

The combination of endocrine therapy (ET) with CDK4/6 inhibitors (CDK4/6i) was the most recent life-changing hallmark in metastatic Luminal breast cancer (BC). However, intrinsic and acquired resistance affect long-term efficacy. Here, we studied the role of receptor activator of nuclear factor-kB (RANK) pathway in CDK4/6i resistance. We found that RANK overexpression in Luminal BC associates with intrinsic resistance to CDK4/6i, both in vitro and in mouse xenografts. Transcriptomic analysis of mouse tumors highlighted decreased proliferation rate and chronic interferon (IFN)-response as resistance drivers. Overall design: The transcriptomic profiles of tumor tissue from MCF-7 and MCF-7 RANK OE xenografts implanted in NSG mice, collected after 21 days of treatment with Vehicle, Palbociclib+Fulvestrant or Palbociclib+Fulvestrant+OPG-Fc, were analyzed by RNASeq. 2-3 tumors per group were included.

内分泌治疗（endocrine therapy, ET）联合CDK4/6抑制剂（CDK4/6 inhibitors, CDK4/6i）是转移性腔面型乳腺癌（metastatic Luminal breast cancer, BC）领域近年来最具里程碑意义的突破性治疗方案。然而，固有耐药（intrinsic resistance）与获得性耐药（acquired resistance）始终限制其长期临床疗效。本研究探讨了核因子κB受体激活剂（receptor activator of nuclear factor-kB, RANK）通路在CDK4/6i耐药中的作用机制。研究结果显示，无论在体外实验还是小鼠异种移植瘤（mouse xenografts）模型中，腔面型乳腺癌组织内的RANK过表达均与CDK4/6i固有耐药显著相关。对小鼠肿瘤组织的转录组学分析（transcriptomic analysis）表明，增殖速率下调与慢性干扰素（interferon, IFN）应答是介导耐药产生的核心驱动因素。本研究的实验设计为：将植入NSG小鼠的MCF-7及MCF-7 RANK过表达（MCF-7 RANK OE）异种移植瘤分为三组，分别给予载体（Vehicle）、帕博西尼（Palbociclib）联合氟维司群（Fulvestrant），或帕博西尼联合氟维司群+OPG-Fc处理，干预21天后采集肿瘤组织，通过RNASeq技术分析其转录组表达谱；每组纳入2-3例肿瘤样本。