Loss of histone lysine methyltransferase EZH2 confers resistance to tyrosine kinase inhibitors in non-small cell lung cancer.

Tyrosine kinase inhibitor (TKI) treatment is the first-line therapy for non-small cell lung cancer (NSCLC) caused by activating mutations of epidermal growth factor receptor (EGFR). However, acquired resistance to EGFR-TKI occurs almost inevitably. Aberrant activation of proto-oncogene MET has been known to confer EGFR-TKI resistance; however, the mechanisms involved remains unclear. Recent evidence implicates epigenetic heterogeneity as playing roles in cancer drug resistance, whereas links involving epigenetic heterogeneity and MET in NSCLC remain poorly understood. We found that expression of EZH2, a histone methyltransferase, was negatively correlated with MET activation and EGFR-TKI resistance in NSCLC cells and clinical samples, suggesting the potential for EZH2 to be used as a biomarker for EGFR-TKI sensitivity. Knockdown or inhibition of EZH2 up-regulated MET expression and phosphorylation, and elevated proliferation and EGFR-TKI resistance of cells in vitro. Meanwhile, inhibition of MET or PI3K/AKT enhanced EZH2 levels and restored sensitivity to EGFR-TKI. These findings indicate a "MET-AKT-EZH2" feedback loop regulating EGFR-TKI-resistance. Furthermore, combination therapy of PI3K/AKT inhibition and EGFR-TKI, which interrupts the loop, enhanced tumor-suppressive effects in an EGFR-TKI-resistant xenograft model, indicating a potential approach against drug resistance in NSCLC.