The development of small-molecule
tyrosine kinase inhibitors (TKI) specific for
epidermal growth factor receptors (EGFR) with activating mutations has led to a new paradigm in the treatment of
non-small cell lung cancer (NSCLC) patients. However, most patients eventually develop resistance.
Hypoxia is a key microenvironmental stress in solid
tumors that is associated with poor prognosis due, in part, to acquired resistance to conventional
therapy. This study documents that long-term, moderate
hypoxia promotes resistance to the EGFR TKI,
gefitinib, in the NSCLC cell line HCC827, which harbors an activating EGFR mutation. Following hypoxic growth conditions, HCC827 cells treated with
gefitinib upregulated
N-cadherin,
fibronectin, and
vimentin expression and downregulated
E-cadherin, characteristic of an epithelial-mesenchymal transition (EMT), which prior studies have linked to EGFR TKI resistance. Mechanistically, knockdown of the
histone demethylases, LSD1 and PLU-1, prevented and reversed
hypoxia-induced
gefitinib resistance, with inhibition of the associated EMT, suggesting that LSD1 and PLU-1 play key roles in
hypoxia-induced
gefitinib resistance and EMT. Moreover,
hypoxia-treated HCC827 cells demonstrated more aggressive
tumor growth in vivo compared with cells grown in normoxia, but inhibition of LSD1 function by
shRNA-mediated knockdown or by the small-molecular inhibitor
SP2509 suppressed
tumor growth and enhanced
gefitinib response in vivo These results suggest that
hypoxia is a driving force for acquired resistance to EGFR TKIs through epigenetic change and coordination of EMT in NSCLC. This study suggests that combination of
therapy with EGFR TKIs and LSD1 inhibitors may offer an attractive therapeutic strategy for NSCLCs. Mol
Cancer Res; 16(10); 1458-69. ©2018 AACR.