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- Title
Inhibiting proliferation of gefitinib-resistant, non-small cell lung cancer.
- Authors
Sudo, Makoto; Chin, Tan; Mori, Seiichi; Doan, Ngan; Said, Jonathan; Akashi, Makoto; Koeffler, H.
- 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.
- Subjects
GEFITINIB; LUNG cancer treatment; DRUG resistance in cancer cells; PROTEIN-tyrosine kinase inhibitors; SOMATIC mutation; EPIDERMAL growth factor receptors; COMBINATION drug therapy; CANCER cell proliferation
- Publication
Cancer Chemotherapy & Pharmacology, 2013, Vol 71, Issue 5, p1325
- ISSN
0344-5704
- Publication type
Article
- DOI
10.1007/s00280-013-2132-y