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

作　　者：Xiaoxiao Liu Xing Zhang Zhiying Shao Xiaorong Zhong Xin Ding Liang Wu Jie Chen Ping He Yan Cheng Kunrui Zhu Dan Zheng Jing Jing Ting Luo 

机构地区：[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

出　　处：《Signal Transduction and Targeted Therapy》2024年第1期295-307,共13页信号转导与靶向治疗（英文）

基　　金：supported by the Sichuan Provincial Department of Science and Technology,International Cooperation in Science and Technology Innovation with Hong Kong,Macao,and Taiwan(2023YFH0095);1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21035);Beijing Xislike Clinical Oncology Research Foundation(Y-HR2020MS-1031);Beijing Science and Technology Innovation Medical Development Foundation(KC2021-JF-0167-13);Key Research and Development Program of Xuzhou(KC20115)。

摘　　要：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.

关 键 词：HER2 SYNERGISTIC TOGETHER 

分 类 号：R737.9[医药卫生—肿瘤]