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

Chen, Hualin; Yang, Donghong; Wang, Yongcun; Tao, Hua; Luo, Yiping; Wu, Aibing; Li, Shujun; Yang, Zhixiong; Chen, Ming

doi:10.7150/jca.63410



International Journal of Biological Sciences

International Journal of Medical Sciences

Theranostics

Journal of Genomics

Nanotheranostics

Global reach, higher impact

Full Text | PDF

J Cancer 2022; 13(3):987-997. doi:10.7150/jca.63410 This issue Cite

Research Paper

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

Hualin Chen¹, Donghong Yang², Yongcun Wang¹, Hua Tao³, Yiping Luo¹, Aibing Wu¹, Shujun Li¹, Zhixiong Yang¹, Ming Chen^4,5✉

1. Department of Pulmonary Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524023, China
2. Department of Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524023, China
3. Department of Radiotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China
4. Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Hangzhou 310011, China
5. Department of Radiation Oncology, Zhejiang Key Lab of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou 310011, China

Citation:

Chen H, Yang D, Wang Y, Tao H, Luo Y, Wu A, Li S, Yang Z, Chen M. Activation of the Hedgehog pathway mediates resistance to epidermal growth factor receptor inhibitors in non-small cell lung cancer. J Cancer 2022; 13(3):987-997. doi:10.7150/jca.63410. https://www.jcancer.org/v13p0987.htm

Other styles

Abstract

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.

Keywords: Sonic Hedgehog Protein, Tyrosine Kinase Inhibitors, Epithelial-Mesenchymal Transition, Non-Small Cell Lung Cancer, Zinc Finger Protein GLI1

Citation styles

APA

Chen, H., Yang, D., Wang, Y., Tao, H., Luo, Y., Wu, A., Li, S., Yang, Z., Chen, M. (2022). Activation of the Hedgehog pathway mediates resistance to epidermal growth factor receptor inhibitors in non-small cell lung cancer. Journal of Cancer, 13(3), 987-997. https://doi.org/10.7150/jca.63410.

ACS

Chen, H.; Yang, D.; Wang, Y.; Tao, H.; Luo, Y.; Wu, A.; Li, S.; Yang, Z.; Chen, M. Activation of the Hedgehog pathway mediates resistance to epidermal growth factor receptor inhibitors in non-small cell lung cancer. J. Cancer 2022, 13 (3), 987-997. DOI: 10.7150/jca.63410.

NLM

CSE

Chen H, Yang D, Wang Y, Tao H, Luo Y, Wu A, Li S, Yang Z, Chen M. 2022. Activation of the Hedgehog pathway mediates resistance to epidermal growth factor receptor inhibitors in non-small cell lung cancer. J Cancer. 13(3):987-997.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.