2. Academic Validation
  3. SLC7A11 protects luminal A breast cancer cells against ferroptosis induced by CDK4/6 inhibitors

SLC7A11 protects luminal A breast cancer cells against ferroptosis induced by CDK4/6 inhibitors

  • Redox Biol. 2024 Aug 10:76:103304. doi: 10.1016/j.redox.2024.103304.
Yingshu Cui 1,  Yi Li 2,  Yuanyuan Xu 3,  Xinxin Liu 4,  Xiaofeng Kang 5,  Junwen Zhu 5,  Shan Long 3,  Yuchen Han 5,  Chunyuan Xue 5,  Zhijia Sun 2,  Yimeng Du 5,  Jia Hu 5,  Lu Pan 5,  Feifan Zhou 6,  Xiaojie Xu 7,  Xiaosong Li 8
Affiliations

Affiliations

  • 1 Medical School of Chinese PLA, Beijing, 100853, China; Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China.
  • 2 Medical School of Chinese PLA, Beijing, 100853, China.
  • 3 Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China.
  • 4 Department of General Surgery, Peking University First Hospital, Beijing, 100034, China.
  • 5 Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100071, China.
  • 6 State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Haikou, 570100, China. Electronic address: zhouff@hainanu.edu.cn.
  • 7 Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100071, China. Electronic address: miraclexxj@126.com.
  • 8 Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China. Electronic address: lixiaosong301@163.com.
PMID: 39153252 DOI: 10.1016/j.redox.2024.103304
Abstract

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.

Keywords

CDK4/6 inhibitors; Ferroptosis; SLC7A11; SP1; Synthetic lethal.

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