Abstract
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Epigenetic alterations have been shown to be involved in NSCLC oncogenesis; however, their function in EGFR-TKI resistance remains uncharacterized. Here, we found that an EHMT2 inhibitor, UNC0638, can significantly inhibit cell growth and induce apoptosis in EGFR-TKI-resistant NSCLC cells. Additionally, we also found that EHMT2 expression and enzymatic activity levels were elevated in EGFR-TKI-resistant NSCLC cells. Moreover, we determined that genetic or pharmacological inhibition of EHMT2 expression enhanced TKI sensitivity and suppressed migration and tumor sphere formation in EGFR-TKI-resistant NSCLC cells. Further investigation revealed that EHMT2 contributed to PTEN transcriptional repression and thus facilitated AKT pathway activation. The negative relationship between EHMT2 and PTEN was confirmed by our clinical study. Furthermore, we determined that combination treatment with the EHMT2 inhibitor and Erlotinib resulted in enhanced antitumor effects in a preclinical EGFR-TKI-resistance model. We also found that high EHMT2 expression along with low PTEN expression can predict poor overall survival in patients with NSCLC. In summary, our findings showed that EHMT2 facilitated EGFR-TKI resistance by regulating the PTEN/AKT pathway in NSCLC cells, suggesting that EHMT2 may be a target in the clinical treatment of EGFR-TKI-resistant NSCLC.
Highlights
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide[1], and treatment failure in patients with the disease is usually attributable to the lack of effectiveness of traditional chemotherapeutic drugs, including platinum and paclitaxel, which mainly induce drug resistance in NSCLC cells[2]
Further study showed that EHMT2 expression and activity levels were upregulated in NSCLC/ER cells, suggesting that EHMT2 plays an important role in EGFR-TKI resistance in NSCLC
The EHMT2 inhibitor UNC0638 was extremely effective in inhibiting cell growth in both PC9/ER and HCC827/ER cells but showed a relatively weak inhibition in their parental cells, suggesting that EHMT2 plays an important role in EGFR-TKI resistance in NSCLC cells
Summary
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide[1], and treatment failure in patients with the disease is usually attributable to the lack of effectiveness of traditional chemotherapeutic drugs, including platinum and paclitaxel, which mainly induce drug resistance in NSCLC cells[2]. Epigenetic phenomena, including DNA methylation and histone modification, have been reported to be involved in NSCLC development and progression[9,10,11]; the role of epigenetic modifications in EGFR-TKI resistance remains poorly understood. To investigate the epigenetic modifications underlying acquired EGFR-TKI resistance in NSCLCs, we administered a series of DNA methylation and histone modification enzyme inhibitors to Erlotinibresistant NSCLC cells (NSCLC/ER). We found that only UNC0638, an inhibitor of the histone lysine methyltransferase EHMT2, significantly inhibited NSCLC/ER cell growth. Further study showed that EHMT2 expression and activity levels were upregulated in NSCLC/ER cells, suggesting that EHMT2 plays an important role in EGFR-TKI resistance in NSCLC. Inhibiting EHMT2 expression reversed Erlotinib resistance in NSCLC/ER cells and attenuated the malignant phenotype of NSCLC/ER cells. Pathological analysis suggested that the balance between PTEN and EHMT2 expression may be a promising predictive biomarker for the prognoses of patients with NSCLC
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