期刊
CANCER BIOLOGY & THERAPY
卷 12, 期 5, 页码 458-465出版社
LANDES BIOSCIENCE
DOI: 10.4161/cbt.12.5.16303
关键词
sunitinib; SU11248; tyrosine kinase inhibitor; molecular targeted therapy; ret-PTC oncoprotein; BRAF protein; papillary thyroid carcinoma; differentiated thyroid cancer
类别
资金
- Seoul National University Bundang Hospital [04-2008-009]
Sunitinib, a multi-targeted tyrosine kinase inhibitor, is frequently incorporated into the management of papillary thyroid carcinoma refractory in standard therapies. Although clinical trials are in progress, the mechanism of action in papillary thyroid carcinomas is not clear, especially regarding the effect on BRAF mutation. We investigated the effect of sunitinib on papillary thyroid carcinoma cells harboring RET/PTC rearrangement and BRAF mutation using TPC-1(M), SNU-790 and B-cPAP cell lines. Cell growth of papillary thyroid cancer cells with RET/PTC rearrangement was effectively inhibited at low doses of sunitinib (IC50 = 0.658 mu M), whereas that of BRAF mutated cells required higher doses. Immunoblotting revealed effective blocking of the MEK/ERK pathway in RET/PTC rearrangement cells, but not in BRAF mutated cells. Cell cycle analysis showed G(1) arrest in RET/PTC rearrangement cells. In vivo orthotopic thyroid cancer mouse model demonstrated statistically significant tumor growth inhibition by sunitinib in RET/PTC rearrangement cancer cells. We conclude that sunitinib effectively inhibits RET/PTC rearrangement cells but not BRAF mutated cells. These data suggest that sunitinib exerts its effect by inhibiting the upstream MAP K signaling cascade. These findings support the unsatisfactory treatment outcomes of sunitinib in many already ongoing clinical trials compared with other tyrosine kinase inhibitors. Clinical application of sunitinib should be directed accordingly.
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