2. Academic Validation
  3. Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer

Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer

  • Signal Transduct Target Ther. 2023 Dec 18;8(1):463. doi: 10.1038/s41392-023-01689-w.
Xiaoxiao Liu # 1 2,  Xing Zhang # 3,  Zhiying Shao # 4,  Xiaorong Zhong # 1,  Xin Ding 2,  Liang Wu 5,  Jie Chen 6,  Ping He 1,  Yan Cheng 1,  Kunrui Zhu 1,  Dan Zheng 1,  Jing Jing 7,  Ting Luo 8
Affiliations

Affiliations

  • 1 Institute for Breast Health Medicine, Cancer Center, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
  • 2 Department of Radiation Oncology, Cancer Center, Affiliated Hospital of Xuzhou Medical University; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, 221000, Xuzhou, China.
  • 3 Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Aachen, 52074, Germany.
  • 4 Cancer Institute, Xuzhou Medical University, 221000, Xuzhou, Jiangsu, China.
  • 5 Division of Nephrology and Transplantation, Department of Internal Medicine, University Medical Center Rotterdam Erasmus MC, Rotterdam, 3015 GD, The Netherlands.
  • 6 Institute for Breast Health Medicine, Department of General Surgery, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
  • 7 Institute for Breast Health Medicine, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China. jingjing@wchscu.cn.
  • 8 Institute for Breast Health Medicine, Cancer Center, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China. luoting@wchscu.cn.
  • # Contributed equally.
PMID: 38110365 DOI: 10.1038/s41392-023-01689-w
Abstract

Human epidermal growth factor receptor 2 (HER2)-positive breast Cancer (BC) has been the most challenging subtype of BC, consisting of 20% of BC with an apparent correlation with poor prognosis. Despite that pyrotinib, a new HER2 inhibitor, has led to dramatic improvements in prognosis, the efficacy of pyrotinib monotherapy remains largely restricted due to its acquired resistance. Therefore, identifying a new potential antitumor drug in combination with pyrotinib to amplify therapeutic efficacy is a pressing necessity. Here, we reported a novel combination of pyrotinib with chrysin and explored its antitumor efficacy and the underlying mechanism in HER2-positive BC. We determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce more evident cell cycle arrest, inhibit the proliferation of BT-474 and SK-BR-3 BC cells, and repress in vivo tumor growth in xenograft mice models. This may be attributed to enhanced Autophagy induced by endoplasmic reticulum stress. Furthermore, the combined treatment of pyrotinib and chrysin induced ubiquitination and glucose-6-phosphate dehydrogenase (G6PD) degradation by upregulating zinc finger and BTB/POZ domain-containing family protein 16 (ZBTB16) in tumorigenesis of BC. Mechanistically, we identified that miR-16-5p was a potential upstream regulator of ZBTB16, and it showed a significant inverse correlation with ZBTB16. Inhibition of miR-16-5p overexpression by restoring ZBTB16 significantly potentiated the overall antitumor efficacy of pyrotinib combined with chrysin against HER2-positive BC. Together, these findings demonstrate that the combined treatment of pyrotinib and chrysin enhances Autophagy in HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis.

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