SLC7A11 protects luminal A breast cancer cells against ferroptosis induced by CDK4/6 inhibitors
Yingshu Cui,
Yi Li,
Yuanyuan Xu,
Xinxin Liu,
Xiaofeng Kang,
Junwen Zhu,
Shan Long,
Yuchen Han,
Chunyuan Xue,
Zhijia Sun,
Yimeng Du,
Jia Hu,
Lu Pan,
Feifan Zhou,
Xiaojie Xu,
Xiaosong Li
Affiliations
Yingshu Cui
Medical School of Chinese PLA, Beijing, 100853, China; Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China
Yi Li
Medical School of Chinese PLA, Beijing, 100853, China
Yuanyuan Xu
Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China
Xinxin Liu
Department of General Surgery, Peking University First Hospital, Beijing, 100034, China
Xiaofeng Kang
Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100071, China
Junwen Zhu
Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100071, China
Shan Long
Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China
Yuchen Han
Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100071, China
Chunyuan Xue
Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100071, China
Zhijia Sun
Medical School of Chinese PLA, Beijing, 100853, China
Yimeng Du
Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100071, China
Jia Hu
Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100071, China
Lu Pan
Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100071, China
Feifan Zhou
State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Haikou, 570100, China; Corresponding author.
Xiaojie Xu
Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100071, China; Corresponding author.
Xiaosong Li
Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, China; Corresponding author. Department of Oncology, the Fifth Medical Center of PLA General Hospital, Beijing, 100071, China.
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.
