Mechanism of intrinsic resistance of lung squamous cell carcinoma to epithelial growth factor receptor-tyrosine kinase inhibitors revealed by high-throughput RNA interference screening.
epithelial growth factor receptor-tyrosine kinase inhibitors
integrin-linked kinase
lung squamous cell carcinoma
Journal
Oncology letters
ISSN: 1792-1074
Titre abrégé: Oncol Lett
Pays: Greece
ID NLM: 101531236
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
12
04
2020
accepted:
24
08
2020
entrez:
2
11
2020
pubmed:
3
11
2020
medline:
3
11
2020
Statut:
ppublish
Résumé
Although targeted therapy has achieved a great breakthrough in the treatment of lung adenocarcinoma, there are still no effective targeted drugs for lung squamous cell carcinoma (SqCC). In addition, as immunotherapy can only prolong the overall survival (OS) of lung SqCC by ≤5 months, chemotherapy and radiotherapy are still the main types of therapy for advanced SqCC. The expression level of epithelial growth factor receptor (EGFR) in patients with lung SqCC is higher compared with those with adenocarcinoma, but the former group is intrinsically resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Therefore, if the drug resistance in patients with lung SqCC could be reversed, the majority of patients may benefit from EGFR-TKIs. In the present study, the high-throughput RNA interference technology was used to screen the genes involved in the EGFR-TKI erlotinib resistance of lung SqCCs, and integrin-linked kinase (ILK) was identified to be the most effective. The role of ILK in erlotinib resistance was further studied in cell lines, and the expression of ILK was analyzed in patients with SqCC and adenocarcinoma. Finally, the mechanism of ILK in EGFR-TKIs resistance was analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and ingenuity pathway analysis (IPA). The results demonstrated that the ILK gene knockdown could overcome erlotinib resistance by inhibiting cell proliferation, inducing apoptosis and blocking the cell cycle at the G2/M phase. The expression of ILK in patients with SqCC was significantly higher compared with those with adenocarcinoma with sensitizing EGFR mutations. In addition, the cell cycle pathway 'G2/M DNA damage and checkpoint regulation' was identified to be significantly inhibited by ILK knockdown in IPA, KEGG and GO analysis. The results of the present study may improve the understanding of EGFR-TKI resistance in lung SqCCs, thus promoting the development of potential targeted therapies for lung SqCCs.
Identifiants
pubmed: 33133263
doi: 10.3892/ol.2020.12218
pii: OL-0-0-12218
pmc: PMC7590427
doi:
Types de publication
Journal Article
Langues
eng
Pagination
363Informations de copyright
Copyright: © Ju et al.
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