Objective: Therapeutic options for patients with dedifferentiated thyroid carcinoma are rare and alternative treatment strategies are needed. Among the most promising new agents for these patients are protein kinase inhibitors like the BRAF- and multi-targeted kinase inhibitor sorafenib. We have already shown that sorafenib inhibits growth of dedifferentiated thyroid carcinoma cell lines with and without BRAF mutation. The purpose of this study was to analyze the molecular effects of sorafenib on cell signalling and cell cycle.
Methods: In thyroid carcinoma cell lines (anaplastic, dedifferentiated follicular and papillary), we analyzed inhibition of signaling molecules of the MAP kinase pathways and of members of the receptor tyrosine kinases after sorafenib treatment by means of phospho-specific antibodies. Flow cytometric cell cycle analyses were performed to investigate cellular effects of sorafenib. Sorafenib was kindly provided by Bayer HealthCare.
Results: After sorafenib treatment, a rapid inhibition of members of the Map-kinase family including MEK1 and MEK2, Erk1 and Erk2 and p38 Map-kinases was achieved. Additionally, members of the Jnk kinase family were inhibited, while the Akt pathway was unaffected. We also detected inhibitory effect of sorafenib on receptor tyrosine kinases like PDGF receptor alpha and beta and VEGF receptors, while EGF receptors and other erbB receptors were not affected. After 4 to 8 h of sorafenib treatment, cells showed apoptosis induction. Cell cycle analyses revealed a sorafenib-dependent arrest mainly in the S phase of the cell cycle in the remaining living cells, while the G0/G1 peak was diminished.
Conclusion: The BRAF- and multi-targeted kinase inhibitor sorafenib showed various inhibitory effects on intracellular signaling pathways in thyroid carcinoma cells and caused cell cycle arrest and apoptosis induction. Since sorafenib was effective in all thyroid carcinoma cell lines independently of the presence of an activating BRAF-mutation, this drug may be a new therapeutic option for dedifferentiated thyroid cancer.
03 - 07 May 2008
European Society of Endocrinology