Open AccessGlycogen synthase kinase‐3 inhibition overcomes epithelial‐mesenchymal transition‐associated resistance to osimertinib in EGFR ‐mutant lung cancer
Author(s) -
Fukuda Koji,
Takeuchi Shinji,
Arai Sachiko,
Kita Kenji,
Tanimoto Azusa,
Nishiyama Akihiro,
Yano Seiji
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14454
Subject(s) - osimertinib , gsk 3 , epithelial–mesenchymal transition , cancer research , lung cancer , gsk3b , epidermal growth factor receptor , erlotinib , biology , glycogen synthase , tyrosine kinase inhibitor , egfr inhibitors , kinase , chemistry , cancer , medicine , phosphorylation , metastasis , biochemistry
Abstract A novel epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor, osimertinib, has marked efficacy in patients with EGFR ‐mutant lung cancer. While epithelial‐mesenchymal transition (EMT) plays a role in the resistance to various targeted drugs, its involvement in EGFR‐inhibitor resistance remains largely unknown. Preclinical experiments with osimertinib‐resistant lung cancer cells showed that EMT was associated with decreased microRNA‐200c and increased ZEB1 expression. In several resistant clone cells, pretreatment with the histone deacetylase inhibitor quisinostat helped overcome the resistance by reverting EMT. Furthermore, drug screening from a library of 100 kinase inhibitors indicated that Glycogen synthase kinase‐3 (GSK‐3) inhibitors, such as LY2090314, markedly inhibited the growth and induced apoptosis of resistant cells, specifically those with a mesenchymal phenotype. These results suggest that GSK‐3 inhibition could be useful to circumvent EMT‐associated resistance to osimertinib in EGFR ‐mutant lung cancer.