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Title: Inhibiting proliferation of gefitinib-resistant, non-small cell lung cancer
Authors: Sudo, M.
Chin, T.M. 
Mori, S.
Doan, N.B.
Said, J.W.
Akashi, M.
Koeffler, H.P.
Keywords: 17-DMAG
Combination chemotherapy
Non-small cell lung cancer (NSCLC)
Tyrosine kinase inhibitor (TKI)
Issue Date: May-2013
Citation: Sudo, M., Chin, T.M., Mori, S., Doan, N.B., Said, J.W., Akashi, M., Koeffler, H.P. (2013-05). Inhibiting proliferation of gefitinib-resistant, non-small cell lung cancer. Cancer Chemotherapy and Pharmacology 71 (5) : 1325-1334. ScholarBank@NUS Repository.
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. © 2013 The Author(s).
Source Title: Cancer Chemotherapy and Pharmacology
ISSN: 03445704
DOI: 10.1007/s00280-013-2132-y
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