Schedule-dependent cytotoxicity of sunitinib and TRAIL in human non-small cell lung cancer cells with or without EGFR and KRAS mutations.
ABSTACT



BACKGROUND
Non-small cell lung cancer (NSCLC) patients who do initially respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) may eventually develop resistance, which may at least partly be due to the acquisition of a secondary EGFR mutation (T790M). Additionally, it has been found that KRAS mutations may serve as poor prognostic biomarkers. Here, we aimed at establishing a suitable treatment regimen for the multi-target TKI sunitinib and the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in NSCLC-derived cells with or without EGFR and KRAS mutations.


METHODS
Four NSCLC-derived cell lines with or without EGFR and KRAS mutations were exposed to different sunitinib and TRAIL treatment regimens. Alterations in cell viability, cell cycle distribution, apoptosis, phosphorylation of AKT and expression of the death receptors DR4 and DR5 were evaluated using CCK8, flow cytometry and Western blotting assays, respectively.


RESULTS
A synergistic cytotoxic effect was observed in all four cell lines treated with sunitinib (1 nM) followed by TRAIL (100 ng/ml), as well as after simultaneous treatment with both agents. We found that sunitinib enhances TRAIL-induced G0/G1-phase cell cycle arrest and blocks TRAIL-triggered activation of AKT as the underlying mechanism. In contrast, we observed antagonistic effects when sunitinib was administered after TRAIL to the cell lines tested. A decreased DR4 and DR5 expression was found to be correlated with this antagonism.


CONCLUSION
From our data we conclude that administration of sunitinib followed by TRAIL, as well as a simultaneous administration of both agents, serve as favorable treatment regimens for NSCLC-derived cells, irrespective of their EGFR and/or KRAS mutation status.
['Bao|Yong-Xia|YX|', 'Zhao|Xiao-Dan|XD|', 'Deng|Hong-Bin|HB|', 'Lu|Chang-Lian|CL|', 'Guo|Yang|Y|', 'Lu|Xing|X|', 'Deng|Li-Li|LL|']
D000971:Antineoplastic Combined Chemotherapy Protocols D017209:Apoptosis D015153:Blotting, Western D002289:Carcinoma, Non-Small-Cell Lung D045744:Cell Line, Tumor D004334:Drug Administration Schedule D019008:Drug Resistance, Neoplasm D066246:ErbB Receptors D018773:Genes, erbB-1 D006801:Humans D007211:Indoles D008175:Lung Neoplasms D009154:Mutation D016283:Proto-Oncogene Proteins p21(ras) D011758:Pyrroles D000077210:Sunitinib D053221:TNF-Related Apoptosis-Inducing Ligand
Sunitinib TRAIL Non-small cell lung cancer Gene mutation Sequential treatment