Activation of the Hedgehog pathway mediates resistance to epidermal growth factor receptor inhibitors in non-small cell lung cancer

• Published in: Journal of Cancer 2022-01, Vol.13 (3), p.987-997
• Main Authors: Chen, Hualin, Yang, Donghong, Wang, Yongcun, Tao, Hua, Luo, Yiping, Wu, Aibing, Li, Shujun, Yang, Zhixiong, Chen, Ming
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1837-9664; 1837-9664
• DOI: 10.7150/jca.63410

The current study aimed to investigate the function of the Hedgehog pathway and its association with epithelial-mesenchymal transition (EMT) in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). Lung tumor tissue specimens from EGFR TKI-resistant patients, including those with brain metastases, had hyperactive Hedgehog signaling compared with those from TKI-sensitive patients. SHH stimulation promoted GLI1 activation as well as cell motility in parental PC9 cells while suppressing gefitinib-induced apoptosis in gefitinib-resistant cells. SHH also promoted EMT in parental PC9 cells via E-cadherin suppression and N-cadherin and vimentin upregulation. The knockdown of GLI1 exhibited the opposite effects. Besides, SHH induced, whereas GLI1 knockdown reversed gefitinib resistance in xenograft tumors. The Hedgehog pathway inhibitor GDC-0449 synergized with gefitinib to increase xenograft tumor sensitivity to chemotherapy and extend survival in tumor-bearing animals. These results suggest the Hedgehog pathway mediates EGFR TKI resistance and induces EMT in NSCLC, representing a potential therapeutic target to defeat TKI resistance.