Daily treatment of BEZ235 significant retarded 8505C xenograft tumor growth during the therapeutic period. The inhibitory effect was less prominent after the discontinuation of therapy, suggesting that prolonged treatment may be necessary to maintain therapeutic 3PO efficacy. BEZ235 significantly degraded caspase-3 in 8505C xenograft tumors, indicating this compound may induce apoptosis in vivo. After discontinuation of BEZ235, the volume of 8505C xenograft tumors subsequently increased. This enlargement of tumor following cessation of therapy might be due to normalization of cell size and resumption of cell MRT68921 (hydrochloride) proliferation, as mTOR and its downstream proteins S6 Kinase 1 and 4E-BP1 play pivotal roles in this respect. No significant weight loss or illness was observed during study period, suggesting that this therapy may have a promising safety profile. A prior report demonstrated that the presence of genetic alterations of PTEN, PIK3CA and AKT1 correlated well with sensitivity to an AKT inhibitor, but had weaker correlations with an mTOR inhibitor. This discrepency suggests that mTOR activity does not depend solely on PI3K/AKT activity. The reported data of genetic alterations in 8 thyroid cancer cell lines was summarized. Limited genetic changes on RAS/RAF/ERK and PI3K/mTOR pathways were identified. The available data do not show any correlation between genetic aberrations of PI3K/mTOR pathways and sensitivity of BEZ235, as no mutation of this pathway in these cell lines reported. Mutations of p53 and BRAF also seem to not be correlated with sensitivity of BEZ235, because both sensitive and less sensitive cell lines harbor the mutations. Exploration of genetic changes of mTOR, the major target of BEZ235, might someday provide information that may predict therapeutic efficacy. Inhibition of mTORC1 may activate the MAPK pathway through a PI3K-dependent feedback loop, which explains why BEZ235 was seen here to activate ERK1/2 in thyroid cancer cells. Combining BEZ235 with an inhibitor targeting MAPK pathway may be a potential approach to enhance therapeutic efficacy. Recently, the combination of a pan-RAF inhibitor and BEZ235 was shown to induce cell cycle arrest at G0/G1 phase, and had beneficial combination effects in treating thyroid cancer. Similarly, in combination of mTOR and MEK inhibitors also demonstrated therapeutic advantage in treating thyroid cancer, providing further evidence that targeting both PI3K/mTOR and MAPK pathways is a potential therapeutic strategy for this disease. For combination therapy experiments, ATC cells were treated with BEZ235 and a chemotherapeutic drug at a fixed dose ratio.
