Activity of mTOR-Inhibitor Rad001 (everolimus) in differentiated and anaplastic thyroid cancer cell lines

Abstract

e14608 Background: Recent data suggest that aberrant activation of PIK3/AKT-pathway and mTOR are involved in the development of thyroid cancer, particularly of anaplastic (ATC) and follicular (FTC) subtype. Therefore, mTOR could be a potential treatment target in thyroid cancer. Methods: To asses the potential role of mTOR as target for the treatment of thyroid cancer, two human ATC cell lines SW1736 and 8505C, the papillary thyroid cancer (PTC) cell line BCPAP and the FTC cell line FTC133 were exposed for 96h to increasing concentrations of the mTOR inhibitor RAD001 (Everolimus, kindly provided by Novartis, Switzerland). For combination experiments 10 nM of RAD001 were combined with increasing concentrations of either doxorubicin (DOX) or cisplatin (CDDP) continuously. Cytotoxicity was measured using the sulforhodamine B assay. IC50-values were calculated with Sigma Plot (Jandel Scientific) and drug interaction was determined by the model of Drewinko. Results: The observed IC50-values of RAD001 were 1nM (FTC133), 10 nM (BCPAP), 1000 nM (SW1736) and 9400 nM (8505C). In contrast to the pronounced differences in sensitivity as assessed on the basis of IC50, a growth inhibitory effect ≥ 25 % was seen in all cell lines at a concentration of 1 nM of RAD001. IC50 for CDDP ranged from 1,3–4,8 μM and for DOX from 8–40 nM. Combination of 10 nM RAD001 with either DOX or CDDP resulted in additive drug interaction with the exception in cell line 8505C where significant synergy was found for the combination with CDDP. Conclusion: RAD001 exerted interesting preclinical activity in two differentiated thyroid cancer cell lines. Mainly additive drug interaction in thyroid cancer cell lines was observed for combinations with CDDP and DOX. Mechanistic investigations are underway and will be presented at the meeting. At least for differentiated thyroid cancer mTOR-inhibition appeared promising, further evaluation in thyroid cancer seems warranted. No significant financial relationships to disclose.