49P - Synergistic effect of histone deacetylase inhibitor in combination with epidermal growth factor receptor tyrosine kinase inhibitor in EGFR-TKI resis...

Date 17 April 2015
Event ELCC 2015
Session Poster lunch
Topics Basic Science
Lung and other Thoracic Tumours
Translational Research
Presenter Xiaohong Han
Citation Annals of Oncology (2015) 26 (suppl_1): 10-14. 10.1093/annonc/mdv045
Authors X. Han, N. Zhang, J. Yao, Y. Shi
  • Department Of Medical Oncology;beijing Key Laboratory Of Clinical Study On Anticancer Molecular Targeted Drugs, Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS), 100021 - Beijing/CN

Abstract

Aim/Background

Currently, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance has become an emerging problem. Therefore, exploring new strategies to overcome drug resistance is the main task of individualized treatment for patients with NSCLC. This study was aimed to investigate the antitumor efficacy of sigle use of histone deacetylase inhibitor (HDACi) or in combination with TKI in TKI-sensitive and resistant NSCLC cell lines.

Methods

Ten NSCLC cell lines with varying mutation status and histology were treated with chidamide (HDACi) and icotinib (TKI) alone or in combination. MTS assays were performed to determine the concentration that inhibits 50% (IC50) value of each drug or the combination. The cytotoxic interaction between the two drugs was evaluted using the combination index (CI) method. The expression level of e-cadherin was determined by western blot analysis.

Results

The results demonstrated that A549 (TKI-resistant, KRAS-mutated), HCC827 (TKI-sensitive, EGFR-mutated), HCC827IR (TKI-resistant, EGFR-mutated) was sensitive to chidamide, the IC50 of these three cell lines was less than 0.5nM and the IC50 of the other seven cell lines was more than 5 µM. We found chidamide increased the sensitivity of icotinib synergistically in EGFR and KRAS wild type cell lines (H292, Calu-3), KRAS mutant cells (A549, H460), and EGFR-TKI resistant EGFR mutant cell lines (H1650, H1650GR, HCC827IR, H1975), but the synergistic effect was the most obvious and meaningful in H1975 cell line (TKI-resistant, harboring EGFR L858R and T790M mutations). Moreover, we found that H460 and Calu-3 had no e-cadherin expression, H1975 had low level of e-cadherin expression, and the other seven cell lines had relatively high levels of e-cadherin expression.

Conclusions

These results suggest that chidamide as a sigle agent exhibits antiproliferative effectives in NSCLC cell lines with EGFR and KRAS mutations. The combination of chidamide and icotinib may be a beneficial treatment strategy for NSCLC with EGFR-T790M mutation. But the role of e-cadherin in the antiproliferative or synergistic mechanisms should be further explored.

Disclosure

All authors have declared no conflicts of interest.