Format

Send to

Choose Destination
See comment in PubMed Commons below
Cancer Chemother Pharmacol. 2013 May;71(5):1325-34. doi: 10.1007/s00280-013-2132-y. Epub 2013 Mar 21.

Inhibiting proliferation of gefitinib-resistant, non-small cell lung cancer.

Author information

1
Cancer Science Institute, National University of Singapore, Singapore, Singapore. makotosudo@live.jp

Abstract

PURPOSE:

Sensitivity to a tyrosine kinase inhibitor (TKI) is correlated with the presence of somatic mutations that affect the kinase domain of epidermal growth factor receptor (EGFR). Development of resistance to TKI is a major therapeutic problem in non-small cell lung cancer (NSCLC). Aim of this study is to identify agents that can overcome TKI resistance in NSCLC.

METHODS:

We used a carefully selected panel of 12 NSCLC cell lines to address this clinical problem. Initially, the cell lines were treated with a variety of 10 compounds. Cellular proliferation was measured via MTT assay. We then focused on the gefitinib-resistant, EGFR mutant cell lines [H1650: exon 19 and PTEN mutations; and H1975: exons 20 (T790M) and 21 (L858R)] to identify agents that could overcome TKI resistance.

RESULTS:

Both 17-DMAG (Hsp90 inhibitor) and belinostat (histone deacetylase inhibitor, HDACi) effectively decreased the growth of almost all NSCLC lines. Also, belinostat markedly decreased the expression of EGFR and phospho-Akt in the cells. Combination of 17-DMAG and belinostat synergistically inhibited in vitro proliferation of these cells. Furthermore, both agents and their combination almost completely prevented TKI-resistant tumor formation (EGFR T790M mutation) in a xenograft model.

CONCLUSION:

These results suggest that the combination of 17-DMAG and belinostat should be examined in a clinical trial for TKI-resistant NSCLC cell.

PMID:
23515752
PMCID:
PMC3636434
DOI:
10.1007/s00280-013-2132-y
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Springer Icon for PubMed Central
    Loading ...
    Support Center