Histone deacetylase inhibitor romidepsin enhances anti-tumor effect of erlotinib in non-small cell lung cancer (NSCLC) cell lines.
BACKGROUND
Most epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs) are sensitive to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib, but many EGFR wild type NSCLCs are resistant to TKIs. In this study, we examined the effects of the histone deacetylase inhibitor, romidepsin, in combination with erlotinib, in NSCLC cell lines and xenografts.


METHODS
For in vitro studies, nine NSCLC cell lines with varying mutation status and histology were treated with erlotinib and romidepsin alone or in combination. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays were performed to determine the concentration that inhibits 50% (IC50) value of each drug or the combination. For in vivo studies, NCI-H1299 xenografts were inoculated subcutaneously into athymic nude mice. Romidepsin and/or erlotinib were injected intraperitoneally after tumors developed and tumor sizes were measured.


RESULTS
We found that romidepsin increased the sensitivity of erlotinib synergistically in all nine NSCLC cell lines including EGFR and KRAS wild type cell lines, KRAS mutant cell lines, and TKI resistant EGFR mutant cell lines. This effect was partially due to enhanced apoptosis. Furthermore, cotreatment of erlotinib and romidepsin inhibited NCI-H1299 xenograft growth in athymic nude mice.


CONCLUSIONS
These observations support a role for the combination of a histone deacetylase inhibitor and a TKI in the treatment of NSCLCs.
Zhang
Wei
W
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Peyton
Michael
M
Xie
Yang
Y
Soh
Junichi
J
Minna
John D
JD
Gazdar
Adi F
AF
Frenkel
Eugene P
EP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000069347:Erlotinib Hydrochloride; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011799:Quinazolines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011799:Quinazolines; C087123:romidepsin; D000069347:Erlotinib Hydrochloride