In addition, intra tumoral heterogeneity with respect to BRAF mutation makes the evaluation of these clinical trials even more complex. kinase inhibitor Seliciclib Poor results were obtained with sorafenib in ATC, although positive results reported with vemura fenib in one ATC with BRAFV600E mutation are worthy to be mentioned. A relevant obstacle to the effi cacy of treatments based on the inhibition of BRAFV600E is the presence of activating mutations of RAS. This proto oncogene is a small GTP binding protein located upstream RAF in the MAPK cascade. Activating muta tions of this protein reactivate the MAPK pathway, mak ing BRAFV600E inhibition inefficient. The high prevalence of RAS activating mutations in ATC makes the inhibition of the MAPK pathway by kinase inhibitors a strategy whose success is unlikely.

Moreover, papillary thyroid carcinoma and ATC exhibit concomi tant BRAFV600E and RAS mutations, although a rare occurrence. In light of these considerations, the pharmacological inhibition of the MAPK pathway looks less promising than the inhibition of the PI3K/Akt/ mTOR pathway. This pathway is constitutively activated by inactivating mutations of PTEN and by activating mutations of PI3KCA. Both mutations are frequent in ATC. Ongoing studies in cells, both in culture and in vivo, are investigating the anticancer effect of the novel allosteric Akt inhibitor, MK2206, in combination with several anticancer agents. This agent selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt path way.

An appealing feature of Akt/mTOR inhibi tors is the possibility of treating advanced thyroid cancer also when resistance to single targeted therapy is con ferred by multiple genetic alterations. Most of the kinase inhibitors currently under investigation are multitargeted inhibitors, with a beneficial double effect impairing the viability of tumor cells and tumor vascularization. The TP53 tumor suppressor gene increases the cyclin kinase inhibitor p21kip1, promoting cell cycle arrest at G1/S. Its inactivation by a mutation impairs the correct modulation of cell proliferation and apoptosis. This gene is mutated in 48% of ATC. The loss of the TP53 mediated control of the apoptotic machinery is probably the most difficult obstacle to overcome for a pharmacological agent to be active in ATC. Beneficial effects in ATC cell lines have been observed with an adenovirus TP53 regulated Cre/loxP system and with a E1B gene defective adenovirus in TP53 mutant cells. Conclusions ATC is characterized by genomic instability that leads to mutations in RET, BRAF, RAS, PTEN, PIK3CA and TP53 genes. The survival of ATC patients has changed little in the past 50 years, despite the introduction of new therapeutic Dacomitinib tools.