Role of HDAC6 in EGFR-TKI Resistance of Non-Small Cell Lung Cancer

[Speaker] Yu-Tsen Lai:1
[Co-author] Ching-Chow Chen:1
1:Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10018, Taiwan

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective targeted-therapy for non-small cell lung cancer (NSCLC) with EGFR-activating mutations. However, acquired resistance leads to treatment failure after a median of 9 to 13 months. Previous studies have indicated that epithelial-mesenchymal transition (EMT) may play a critical role in metastasis and also confer to acquired resistance in NSCLC. Since EMT is a plastic state, the driving force of EMT is likely to change chromatin accessibility or modulate cellular signaling pathways rather than induce genetic mutations. We hypothesize that histone deacetylase 6 (HDAC6), a member of HDAC protein family, highly expressing in various malignant tumors may regulate EMT.

We generated gefitinib (HCC827/IR) and AZD-9291 (H1975/AR) acquired resistant NSCLC cells to investigate the mechanism of drug resistance. Effect of HDAC6 selective inhibitor (HDAC6i) ACY-1215 on both resistant cells was evaluated by migration assay, colony formation and sphere formation. In addition, the sensitivity of gefitinib or AZD-9291 was examined in HDAC6i-treated cells.

Both HCC827/IR and H1975/AR lost cell polarity and gained mesenchymal-like characteristics, accompanied by down-regulation of E-cadherin and up-regulation of Vimentin. Meanwhile, increased HDAC6 and decreased α-tubulin acetylation were found in both resistant cells compared with parental cells. ACY-1215 downregulated HDAC6 dose-dependently and restored E-cadherin in both TKI-resistant cells, accompanied by upregulation of α-tubulin acetylation.

Positive correlation between HDAC6 and Vimentin during EMT suggests that HDAC6 might be a biomarker for TKI-resistant NSCLC. ACY-1215 inhibiting the protein level of HDAC6 shows great potential to overcome the therapeutic limit of NSCLC.

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