Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) can significantly extend tumor response in patients with metastatic luminal A breast cancer, yet intrinsic and acquired resistance remains a prevalent issue. Understanding the molecular features of CDK4/6 inhibitor sensitivity and the potential efficacy of their combination with novel targeted cell death inducers may lead to improved patient outcomes. Herein, we demonstrate that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, partly underpins the efficacy of CDK4/6 inhibitors. Mechanistically, CDK4/6 inhibitors downregulate the cystine transporter SLC7A11 by inhibiting SP1 binding to the SLC7A11 promoter region. Furthermore, SLC7A11 is identified as critical for the intrinsic sensitivity of luminal A breast cancer to CDK4/6 inhibitors. Both genetic and pharmacological inhibition of SP1 or SLC7A11 enhances cell sensitivity to CDK4/6 inhibitors and synergistically inhibits luminal A breast cancer growth when combined with CDK4/6 inhibitors in vitro and in vivo. Our data highlight the potential of targeting SLC7A11 in combination with CDK4/6 inhibitors, supporting further investigation of combination therapy in luminal A breast cancer.

中文翻译：

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SLC7A11 保护 Luminal A 乳腺癌细胞免受 CDK4/6 抑制剂诱导的铁死亡


细胞周期蛋白依赖性激酶 4 和 6 抑制剂（CDK4/6 抑制剂）可显着延长转移性管腔 A 型乳腺癌患者的肿瘤反应，但内在和获得性耐药仍然是一个普遍问题。了解 CDK4/6 抑制剂敏感性的分子特征及其与新型靶向细胞死亡诱导剂组合的潜在功效可能会改善患者的预后。在此，我们证明铁死亡是一种由铁依赖性磷脂过氧化驱动的受调节细胞死亡形式，在一定程度上支撑了 CDK4/6 抑制剂的功效。从机制上讲，CDK4/6 抑制剂通过抑制 SP1 与 SLC7A11 启动子区域的结合来下调胱氨酸转运蛋白 SLC7A11。此外，SLC7A11 被认为对于 Luminal A 乳腺癌对 CDK4/6 抑制剂的内在敏感性至关重要。 SP1 或 SLC7A11 的遗传和药理学抑制可增强细胞对 CDK4/6 抑制剂的敏感性，并在体外和体内与 CDK4/6 抑制剂联合使用时协同抑制 Luminal A 乳腺癌生长。我们的数据强调了靶向 SLC7A11 与 CDK4/6 抑制剂联合的潜力，支持对 Luminal A 乳腺癌联合治疗的进一步研究。