Blockade of Hedgehog Signaling Synergistically Increases Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Cell Lines

• Published in: PloS one Vol. 11; no. 3; p. e0149370
• Main Authors: Bai, Xiao-Yan, Zhang, Xu-Chao, Yang, Su-Qing, An, She-Juan, Chen, Zhi-Hong, Su, Jian, Xie, Zhi, Gou, Lan-Ying, Wu, Yi-Long
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.03.2016; Public Library of Science (PLoS)
• Subjects: ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - metabolism; Biology and Life Sciences; Biomarkers; Biomarkers, Tumor - metabolism; Cadherins - metabolism; Cancer; Cancer therapies; Carcinogenesis; Carcinoma, Non-Small-Cell Lung - metabolism; Care and treatment; Cell activation; Cell growth; Cell Line; Cell Line, Tumor - drug effects; Cell Proliferation; Cellular signal transduction; Down-Regulation; Drug resistance; Drug Resistance, Neoplasm; E-cadherin; Embryogenesis; Embryonic growth stage; Epidermal growth factor; Epidermal growth factor receptors; Gefitinib; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Hedgehog protein; Hedgehog Proteins - metabolism; Humans; Hyperactivity; Immunoglobulins; Immunohistochemistry; Inhibitory Concentration 50; Kinases; Ligands; Lung cancer; Lung cancer, Non-small cell; Lung diseases; Lung Neoplasms - metabolism; Medicine and Health Sciences; Mesenchyme; Mutation; Neoplasm Proteins - metabolism; Neoplastic Stem Cells - metabolism; Non-small cell lung carcinoma; Oncology; Physiological aspects; Prostate; Protein Kinase Inhibitors - pharmacology; Protein tyrosine kinase; Protein-tyrosine kinase receptors; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Research and Analysis Methods; Rodents; Science; Sensitivity; Signal Transduction; Signaling; Snail Family Transcription Factors; Stem cells; Transcription Factors - metabolism; Treatment resistance; Tumor cell lines; Tumorigenesis; Tyrosine; Up-Regulation; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0149370

Aberrant activation of the hedgehog (Hh) signaling pathway has been implicated in the epithelial-to-mesenchymal transition (EMT) and cancer stem-like cell (CSC) maintenance; both processes can result in tumor progression and treatment resistance in several types of human cancer. Hh cooperates with the epidermal growth factor receptor (EGFR) signaling pathway in embryogenesis. We found that the Hh signaling pathway was silenced in EGFR-TKI-sensitive non-small-cell lung cancer (NSCLC) cells, while it was inappropriately activated in EGFR-TKI-resistant NSCLC cells, accompanied by EMT induction and ABCG2 overexpression. Upregulation of Hh signaling through extrinsic SHH exposure downregulated E-cadherin expression and elevated Snail and ABCG2 expression, resulting in gefitinib tolerance (P < 0.001) in EGFR-TKI-sensitive cells. Blockade of the Hh signaling pathway using the SMO antagonist SANT-1 restored E-cadherin expression and downregulate Snail and ABCG2 in EGFR-TKI-resistant cells. A combination of SANT-1 and gefitinib markedly inhibited tumorigenesis and proliferation in EGFR-TKI-resistant cells (P < 0.001). These findings indicate that hyperactivity of Hh signaling resulted in EGFR-TKI resistance, by EMT introduction and ABCG2 upregulation, and blockade of Hh signaling synergistically increased sensitivity to EGFR-TKIs in primary and secondary resistant NSCLC cells. E-cadherin expression may be a potential biomarker of the suitability of the combined application of an Hh inhibitor and EGFR-TKIs in EGFR-TKI-resistant NSCLCs.