The PI3K/mTOR pathway is important for cell metabolism survi

The PI3K/mTOR LLY-507 pathway is important for cell metabolism survival and proliferation. Class IA PI3Ks are heterodimers containing a p85 regulatory and a p110 catalytic subunits which phosphorylate phosphatidylinositol-4,5-biphosphate, yielding phosphatidylinositol-3,4,5-triphosphate. PIP3 combines with phosphoinositide-dependent protein kinase 1 to phosphorylate AKT at Thr308. In addition, the phosphorylation of AKT at Ser 473 by mTORC2 is required for full activity of AKT. Activation of AKT phosphorylates mTORC1, which subsequently phosphorylates S6 kinase1 and 4E-BP1, leading to G1/S cell cycle progression and inhibition of apoptosis. PTEN is a tumor suppressor that dephosphorylates PIP3 and inactivates this pathway. Alterations of this signaling pathway frequently occur in malignancies and are potential targets for cancer therapy. In thyroid cancer, genetic alterations affecting the PI3K/mTOR pathway have been identified. PIK3CA copy number gain correlates with increased PIK3CA protein expression. PIK3CA copy number gain occurs more frequently than genetic 1242156-23-5 mutations of PIK3CA or PTEN in thyroid cancer. More PIK3CA/AKT1 mutations and PIK3CA copy gain are identified in ATC as compared to well differentiated cancer, suggesting that PI3K/mTOR pathway activity is involved in the process of cancer de-differentiation. For MTC, RET proto-oncogene mutations occur in almost all familiar cases and about half of sporadic MTC. This gain-offunction rearrangement enhances PI3K/mTOR signaling transduction. In sporadic MTC without RET mutations, over 50% of tumor samples show activation of AKT or mTOR by immunohistochemistry. BEZ235 is a dual PI3K/mTOR inhibitor that reduces PI3K and mTOR kinase activity by competitive binding to the ATPbinding cleft of these enzymes. BEZ235 may treat cancers through induction of G0/G1 cell cycle arrest and apoptosis, and has recently entered phase II clinical trials. This study was conducted to evaluate the efficacy of BEZ235 in treating thyroid cancer from four major pathological types, including PTC, FTC, ATC and MTC. We also explored combination effects of BEZ235 and currently employed chemotherapeutics against four ATC cell lines. The inhibition of the PI3K/mTOR pathway may also lead to apoptosis. The ability of BEZ235 to c