title: Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo.
abstract: Mammalian target of rapamycin (mTOR)in renal cell carcinoma (RCC) represents a valuable oncotarget for treatment. We here tested the potential anti-RCC activity by a novel mTOR kinase inhibitor WYE-687in vitro and in vivo.WYE-687 was cytotoxic and anti-proliferative to established RCC cell lines (786-O and A498) and primary human RCC cells. Yet, it was non-cytotoxic toHK-2 tubular epithelial cells.WYE-687 provoked caspase-dependent apoptosis in the RCC cells. At the molecular level, WYE-687 almost completely blocked mTORC1 (p-S6K1 and p-S6) and mTORC2 (p-Akt Ser 473) activation in both 786-Ocells and primary human RCC cells, where it downregulated both hypoxia-inducible factor (HIF)-1α and HIF-2α expression. Significantly, oral administration of WYE-687 potently suppressed786-O tumor xenograft growth in nude mice. mTORC1/2 activation and HIF-1α/2α expression were also remarkably downregulated in WYE-687-treated tumor tissues. Thus, our preclinical results imply that WYE-687 may have important translational value for the treatment of RCC.
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Pan
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Gu
authors.affiliation: Department of pathophysiology, Nantong University School of Medicine, Nantong, China.
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Mao
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.affiliation: The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Shan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D011720:Pyrazoles; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C000608239:WYE-687