Pyrotinib Targeted EGFR-STAT3/CD24 Loop-Mediated Cell Viability in TSC

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 19; p. 3064
• Main Authors: Han, Xiao, Zhang, Yupeng, Li, Yin, Lin, Zhoujun, Pei, Xiaolin, Feng, Ya, Yang, Juan, Li, Fei, Li, Tianjiao, Fu, Zhenkun, Wang, Changjun, Li, Chenggang
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.09.2022; MDPI
• Subjects: Acrylamides; Aminoquinolines; Antibodies; Apoptosis; Biotechnology; Breast cancer; Cancer therapies; CD24; CD24 Antigen; Cell cycle; Cell growth; Cell proliferation; Cell Survival; Cell viability; Drug targeting; Drug therapy; EGFR/STAT3 signaling; Enzyme inhibitors; Epidermal growth factor; Epidermal growth factor receptors; ErbB protein; ErbB Receptors; ErbB-2 protein; Gene expression; Humans; Immune checkpoint; Kinases; Methods; Mutation; Nuclear transport; Pilot Projects; Protein Kinase Inhibitors; Protein-tyrosine kinase receptors; Proteins; pyrotinib; Smooth muscle; Software; Stat3 protein; STAT3 Transcription Factor; TSC2; Tuberous sclerosis; Tuberous Sclerosis Complex 2; China; United States > US; TSC2; CD24; EGFR/STAT3 signaling; pyrotinib
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11193064

Pyrotinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor, designed for the therapy of HER2-positive breast cancers. Inhibition of the epidermal growth factor receptor (EGFR, HER family) efficiently and selectively suppresses the proliferation of human TSC2-deficient smooth muscle cells and reverses lung changes in LAM/TSC. Our pilot study indicated that pyrotinib dramatically restrained the vitality of TSC2-deficient cells compared to its limited impact on TSC2-expression cells. Pyrotinib induced G1-phase arrest and triggered apoptosis by blocking abnormally activated CD24 in TSC2-deficient cells. CD24 is not only an important immune checkpoint, but is also involved in the regulation of signaling pathways. Pyrotinib inhibited the nuclear import of pEGFR and restrained the pEGFR/pSTAT3 signals, which directly boosted the transcriptional expression of CD24 by binding to its promoter region. In reverse, CD24 enhanced pEGFR function by directly binding. Pyrotinib specifically targeted TSC2-deficient cells, inhibited tumor cell viability and induced apoptosis through EGFR-STAT3/CD24 Loop in vivo and in vitro. Thus, pyrotinib may be a promising new therapeutic drug for TSC treatment.