Background: c-Myc is overexpressed in different types of cancer, including 
thyroid cancer, and has been considered undruggable. There is evidence showing 
that MLN8237, a type of aurora A kinase (AURKA) inhibitor, destabilizes c-Myc 
proteins in liver cancer cells through disruption of the c-Myc/AURKA complex. 
However, the role of MLN8237 in thyroid cancer remains largely unclear. The aims 
of this study were to test the therapeutic potential of MLN8237 in thyroid 
cancer, and to analyze determinant factors affecting the response of thyroid 
cancer cells to MLN8237 and clarify the corresponding mechanism. Methods: The 
phenotypic effects of MLN8237 in thyroid cancer cells were evaluated through a 
series of in vitro and in vivo experiments, and the mechanism of c-Myc affecting 
MLN8237 response were explored using Western blot, ubiquitination, and 
cycloheximide chase assays. Results: The data show that the levels of c-Myc 
protein were strongly associated with MLN8237 cellular response in thyroid 
cancer cells. Only the cells with high c-Myc expression exhibited growth 
inhibition upon MLN8237 treatment. However, MLN8237 barely affected the growth 
of those with low c-Myc expression. Mechanistically, MLN8237 dramatically 
promoted proteasomal degradation of c-Myc proteins through disruption of the 
c-Myc/AURKA complex in the cells with high c-Myc expression. A similar antitumor 
activity of MLN8237 was also found in xenograft tumor models. Conclusions: The 
data demonstrate that c-Myc is a major determinant for MLN8237 responsiveness in 
thyroid cancer cells. Thus, indirectly targeting c-Myc by MLN8237 may be an 
effective strategy for thyroid cancer overexpressing c-Myc.